MEpedia - User contributions [en]

Interleukin 17

2020-01-07T22:44:04Z

Mbunke:

Interleukin 17A is a pro-inflammatory cytokine.

Recent research has led some to believe that IL-17 may have a significant role in the development and persistence of autism through its inflammatory effects on the brain. Inspired by the observation that fever often temporarily reduces the behavioral deficits in autistic children, researchers discovered it may be the production of IL-17 during the fever state that causes these changes.

Though cytokines are immune-modulating agents, IL-17 was shown in one study to work like a neuro-modulator in mice with autism-like behavioral changes, having the paradoxical effects of increased risk of behavioral changes when exposed in-utero to maternal IL-17, but decreased behavioral abnormalities in adult mice.<ref>{{Cite journal|last=Reed|first=Michael Douglas|last2=Yim|first2=Yeong Shin|last3=Wimmer|first3=Ralf D.|last4=Kim|first4=Hyunju|last5=Ryu|first5=Changhyeon|last6=Welch|first6=Gwyneth Margaret|last7=Andina|first7=Matias|last8=King|first8=Hunter Oren|last9=Waisman|first9=Ari|date=2019-12-18|title=IL-17a promotes sociability in mouse models of neurodevelopmental disorders|url=https://www.nature.com/articles/s41586-019-1843-6|journal=Nature|language=en|pages=1–5|doi=10.1038/s41586-019-1843-6|issn=1476-4687}}</ref> The mechanism by which IL-17 seemed to create these changes was by affecting the brain region S1DZ, part of the somatosensory cortex that is likely responsible for sensing where the body is in space.

In reference to IL-17's role in the brain, one researcher from the latter study said, “What’s fascinating about this communication is the immune system directly sends its messengers to the brain, where they work as if they’re brain molecules, to change how the circuits work and how the behaviors are shaped.”<ref>{{Cite web|url=http://news.mit.edu/2019/explain-infections-fever-reduce-autism-1218|title=Study may explain how infections reduce autism symptoms|website=MIT News|access-date=2020-01-07}}</ref> These findings may be significant to people with M.E. because they demonstrate the role of inflammation and immune-modulated cytokines on the central nervous system and behavior.

Further studies have demonstrated the importance of IL-17 production by gut bacteria in the modulation of autism as well, which may also hold clues for those who suspect their M.E. symptoms to be due to neuro-inflammation and/or the result of an infection.<ref>{{Cite journal|last=Atladóttir|first=Hjördís Ósk|last2=Thorsen|first2=Poul|last3=Schendel|first3=Diana E.|last4=Østergaard|first4=Lars|last5=Lemcke|first5=Saane|last6=Parner|first6=Erik T.|date=2010-05-03|title=Association of Hospitalization for Infection in Childhood With Diagnosis of Autism Spectrum Disorders: A Danish Cohort Study|url=https://jamanetwork.com/journals/jamapediatrics/fullarticle/383197|journal=Archives of Pediatrics & Adolescent Medicine|language=en|volume=164|issue=5|pages=470–477|doi=10.1001/archpediatrics.2010.9|issn=1072-4710}}</ref><ref>{{Cite web|url=https://www.sciencedaily.com/releases/2019/04/190409093725.htm|title=Autism symptoms reduced nearly 50 percent two years after fecal transplant|website=ScienceDaily|language=en|access-date=2020-01-07}}</ref>

==Learn more ==

==See also==

* [[Cytokine]]

==References==
<references />

[[Category:Body systems]]
[[Category:Cytokines]]

Interleukin 17

2020-01-07T22:37:27Z

Mbunke:Added information from a few studies on IL-17 and neuro-inflammation

Interleukin 17A is a pro-inflammatory cytokine. Recent research has led some to believe that IL-17 may have a significant role in the development and persisting symptoms of autism through its inflammatory effects on the brain. Though cytokines are immune-modulating agents, IL-17 was shown in one study to work like a neuro-modulator in mice with autism-like behavioral changes, having the paradoxical effects of increased risk of behavioral changes when exposed in-utero to maternal IL-17, but decreased behavioral abnormalities in adult mice.<ref>{{Cite journal|last=Reed|first=Michael Douglas|last2=Yim|first2=Yeong Shin|last3=Wimmer|first3=Ralf D.|last4=Kim|first4=Hyunju|last5=Ryu|first5=Changhyeon|last6=Welch|first6=Gwyneth Margaret|last7=Andina|first7=Matias|last8=King|first8=Hunter Oren|last9=Waisman|first9=Ari|date=2019-12-18|title=IL-17a promotes sociability in mouse models of neurodevelopmental disorders|url=https://www.nature.com/articles/s41586-019-1843-6|journal=Nature|language=en|pages=1–5|doi=10.1038/s41586-019-1843-6|issn=1476-4687}}</ref> The mechanism by which IL-17 seemed to create these changes was by affecting the brain region S1DZ, part of the somatosensory cortex that is likely responsible for sensing where the body is in space.

In reference to IL-17's role in the brain, one researcher from the latter study said, “What’s fascinating about this communication is the immune system directly sends its messengers to the brain, where they work as if they’re brain molecules, to change how the circuits work and how the behaviors are shaped.”<ref>{{Cite web|url=http://news.mit.edu/2019/explain-infections-fever-reduce-autism-1218|title=Study may explain how infections reduce autism symptoms|website=MIT News|access-date=2020-01-07}}</ref> These findings may be significant to people with M.E. because they demonstrate the role of inflammation and immune-modulated cytokines on the central nervous system and behavior.

Further studies have demonstrated the importance of gut-residing bacteria in the modulation of autism as well, including their role on IL-17 production, which may also hold clues for those who suspect their M.E. symptoms to be due to neuro-inflammation and/or the result of an infection.<ref>{{Cite journal|last=Atladóttir|first=Hjördís Ósk|last2=Thorsen|first2=Poul|last3=Schendel|first3=Diana E.|last4=Østergaard|first4=Lars|last5=Lemcke|first5=Saane|last6=Parner|first6=Erik T.|date=2010-05-03|title=Association of Hospitalization for Infection in Childhood With Diagnosis of Autism Spectrum Disorders: A Danish Cohort Study|url=https://jamanetwork.com/journals/jamapediatrics/fullarticle/383197|journal=Archives of Pediatrics & Adolescent Medicine|language=en|volume=164|issue=5|pages=470–477|doi=10.1001/archpediatrics.2010.9|issn=1072-4710}}</ref><ref>{{Cite web|url=https://www.sciencedaily.com/releases/2019/04/190409093725.htm|title=Autism symptoms reduced nearly 50 percent two years after fecal transplant|website=ScienceDaily|language=en|access-date=2020-01-07}}</ref>

==Learn more ==

==See also==

* [[Cytokine]]

==References==
<references />

[[Category:Body systems]]
[[Category:Cytokines]]

Menstrual cycle

2019-08-09T06:27:17Z

Mbunke:/* Cycles and phases */ fixed typos

The [[menstrual cycle]] plays a role in the variation of symptoms and symptom severity in many [[immunological]], [[neurological]], and [[female predominant diseases]].

== Cycles and phases ==

=== Follicular Phase ===
At the beginning of a woman's cycle, the hypothalamus begins to secrete Gonadotropin Releasing Hormone (GnRH), stimulating the pituitary to create Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH), which travel to the ovaries. FSH causes follicles in the ovaries to begin to mature. Several follicles, each of which stores an egg, begin to grow as they mature, and in the process release estrogen. This estrogen produces a negative feedback during the first 10 days of the cycle that tells to the pituitary to inhibit the release of LH. It is important to note that ''low'' levels of estrogen will inhibit the release of LH from the pituitary, while ''high'' levels will stimulate it.

=== Ovulation ===
As estrogen continues to rise due to the maturing follicles, it also causes FSH levels to fall steadily (''low'' estrogen levels trigger the release of FSH). Around day 10 of the cycle, estrogen levels reach a threshold which stops the negative feedback of LH and begins a positive one resulting in the secretion of LH by the pituitary. The resulting spike in LH triggers the most mature follicle to release an egg (or oocyte); this is called ovulation.

=== Luteal Phase ===
After ovulation, the empty follicle will begin to die. This dying follicle is called a corpus luteum. As the corpus luteum degrades, it secretes three hormones: estrogen, inhibin, and progesterone. Inhibin provides a negative feedback to the pituitary to suppress the production of FSH. Progesterone provides a similar feedback to prohibit the release of GnRH, which in turn decreases the levels of LH and FSH. It also stimulates endometrial growth (the interior lining of the uterus).

As the corpus luteum degenerates, it will secrete fewer and fewer hormones, and progesterone, estrogen, and inhibin will steadily decrease. In the absence of fertilization, the decreasing levels of progesterone can no longer maintain the lining of the uterine wall, so the wall dies and sheds out of the body, resulting in menstruation. This decrease in progesterone also allows for the secretion of GnRH to begin again, and the cycle repeats.<ref>{{Cite journal|last=Reed|first=Beverly G.|last2=Carr|first2=Bruce R.|date=2000|editor-last=Feingold|editor-first=Kenneth R.|editor2-last=Anawalt|editor2-first=Bradley|editor3-last=Boyce|editor3-first=Alison|editor4-last=Chrousos|editor4-first=George|editor5-last=Dungan|editor5-first=Kathleen|editor6-last=Grossman|editor6-first=Ashley|editor7-last=Hershman|editor7-first=Jerome M.|editor8-last=Kaltsas|editor8-first=Gregory|editor9-last=Koch|editor9-first=Christian|title=The Normal Menstrual Cycle and the Control of Ovulation|url=http://www.ncbi.nlm.nih.gov/books/NBK279054/|location=South Dartmouth (MA)|publisher=MDText.com, Inc.|pmid=25905282}}</ref>

== Immune changes ==

Populations of [[Treg]]s increase peak just before ovulation and bottom out during the [[luteal phase]], just before [[menstruation]].{{Citation needed}}

[[Progesterone]] and [[estrogen]] have [[anti-inflammatory]] effects.{{Citation needed}}

==Health effects in ME/CFS ==

Women with [[chronic fatigue syndrome]] report higher rates of [[polycystic ovarian syndrome]] (PCOS) and anovulatory cycles, higher rates of [[dysmenorrhea]] and higher rates of [[endometriosis]].<ref name=":0">{{Cite journal|last=Allen|first=Peggy Rosati|date=Jul 2008|title=Chronic fatigue syndrome: implications for women and their health care providers during the childbearing years|url=https://www.ncbi.nlm.nih.gov/pubmed/18586181|journal=Journal of Midwifery & Women's Health|volume=53|issue=4|pages=289–301; quiz 399|doi=10.1016/j.jmwh.2007.12.001|issn=1542-2011|pmid=18586181}}</ref>

Women who develop CFS report at higher rates a history of irregular cycles, [[amenorrhea]], [[anovolutory]] cycles and sporadic bleeding between periods.<ref>{{Cite journal|last=Komaroff|first=AnthonyL|last2=Dailey|first2=Christine|last3=Hall|first3=JanetE|last4=Signorello|first4=LisaB|last5=Harlow|first5=BernardL|date=1998-09-28|title=Reproductive correlates of chronic fatigue syndrome|url=https://www.amjmed.com/article/S0002-9343(98)00173-9/abstract|journal=The American Journal of Medicine|language=English|volume=105|issue=3|pages=94S–99S|doi=10.1016/S0002-9343(98)00173-9|issn=0002-9343}}</ref>

Numerous outbreaks of [[epidemic myalgic encephalomyelitis]] noted menstrual irregularities and a tendency toward relapse before or during menstruation.<ref name="Shelokov, 1957">{{Citation
| last1 = Shelokov | first1 = Alexis | authorlink1 =
| last2 = Habel | first2 = Karl | authorlink2 =
| last3 = Verder | first3 = Elizabeth | authorlink3 =
| last4 = Welsh | first4 = William | authorlink4 =
| title = Epidemic Neuromyasthenia — An Outbreak of Poliomyelitis-like Illness in Student Nurses
| journal = New England Journal of Medicine | volume = 1957 | issue = 257 | page = 345-355
| date = August 1957
| doi = 10.1056/NEJM195708222570801
}}</ref><ref name=":1">{{Cite journal|last=Albrecht|first=Robert|date=March 21, 1964|title=Epidemic Neuromyasthenia Outbreak in a Convent in New York State|url=https://www.ncbi.nlm.nih.gov/pubmed/14100144|journal=Journal of the American Medical Association|volume=187|pages=904-907|via=}}</ref><ref name="Poskanzer, 19572">{{Citation
| last1 = Poskanzer | first1 = David C. | authorlink1 =
| last2 = Henderson | first2 = Donald A. | authorlink2 =
| last3 = Kunkle | first3 = E. Charles | authorlink3 =
| last4 = Kalter | first4 = Seymour S. | authorlink4 =
| last5 = Clement | first5 = Walter B. | authorlink5 =
| last6 = Bond | first6 = James O. | authorlink6 =
| title = Epidemic Neuromyasthenia — An Outbreak in Punta Gorda, Florida
| journal = New England Journal of Medicine | volume = 1957 | issue = 257 | page = 356-364
| date = 1957
| pmid = 13464939
| doi = 10.1056/NEJM195708222570802
| url = http://www.nejm.org/doi/full/10.1056/NEJM195708222570802
}}</ref>

== Health effects in other conditions ==

The menstrual cycle can have effects on the timing and severity of symptoms of women suffering from many different conditions, including [[epilepsy]], [[migraine]]s, [[asthma]], [[rheumatoid arthritis]] and [[irritable bowel syndrome]].<ref name=":2">{{Cite journal|last=Reid|first=Robert L.|last2=Case|first2=Allison M.|date=1998-07-13|title=Effects of the Menstrual Cycle on Medical Disorders|url=https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/208109|journal=Archives of Internal Medicine|language=en|volume=158|issue=13|pages=1405–1412|doi=10.1001/archinte.158.13.1405|issn=0003-9926}}</ref>

Many women with [[epilepsy]] have patterns of seizure activity linked to their menstrual cycles, called [[catamenial epilepsy]].<ref>{{Cite journal|last=Herzog|first=Andrew G.|date=2008-03-01|title=Catamenial epilepsy: Definition, prevalence pathophysiology and treatment|url=https://www.seizure-journal.com/article/S1059-1311(07)00233-6/abstract|journal=Seizure - European Journal of Epilepsy|language=English|volume=17|issue=2|pages=151–159|doi=10.1016/j.seizure.2007.11.014|issn=1059-1311|pmid=18164632}}</ref><ref>{{Cite journal|last=Herzog|first=Andrew G.|last2=Harden|first2=Cynthia L.|last3=Liporace|first3=Joyce|last4=Pennell|first4=Page|last5=Schomer|first5=Donald L.|last6=Sperling|first6=Michael|last7=Fowler|first7=Kristen|last8=Nikolov|first8=Blagovast|last9=Shuman|first9=Sevie|date=2004|title=Frequency of catamenial seizure exacerbation in women with localization-related epilepsy|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.20214|journal=Annals of Neurology|language=en|volume=56|issue=3|pages=431–434|doi=10.1002/ana.20214|issn=1531-8249}}</ref><ref>{{Cite journal|last=Herzog|first=Andrew G.|last2=Klein|first2=Pavel|last3=Rand|first3=Bernard J.|date=1997|title=Three Patterns of Catamenial Epilepsy|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1528-1157.1997.tb01197.x|journal=Epilepsia|language=en|volume=38|issue=10|pages=1082–1088|doi=10.1111/j.1528-1157.1997.tb01197.x|issn=1528-1167}}</ref><ref>http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2006.00672.x/abstract</ref> Seizure activity increases just before ovulation and just before menstruation.<ref>{{Cite journal|last=Reid|first=Robert L.|last2=Case|first2=Allison M.|date=1998-07-13|title=Effects of the Menstrual Cycle on Medical Disorders|url=https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/208109|journal=Archives of Internal Medicine|language=en|volume=158|issue=13|pages=1405–1412|doi=10.1001/archinte.158.13.1405|issn=0003-9926}}</ref>

Abrupt estrogen withdrawal, such as what occurs just prior to menstruation, can trigger [[migraine]]s.<ref>{{Cite journal|last=Brandes|first=Jan Lewis|date=2006-04-19|title=The Influence of Estrogen on Migraine: A Systematic Review|url=https://jamanetwork.com/journals/jama/fullarticle/202685|journal=JAMA|language=en|volume=295|issue=15|pages=1824–1830|doi=10.1001/jama.295.15.1824|issn=0098-7484}}</ref><ref name=":2" /> Women with [[rheumatoid arthritis]] experienced reduced symptoms after ovulation, owing potentially to the anti-inflammatory effects of [[progesterone]] and [[estrogen]].<ref>{{Cite journal|last=Latman|first=Neal S.|date=1983-06-01|title=Relation of menstrual cycle phase to symptoms of rheumatoid arthritis|url=https://www.amjmed.com/article/0002-9343(83)90789-1/abstract|journal=The American Journal of Medicine|language=English|volume=74|issue=6|pages=957–960|doi=10.1016/0002-9343(83)90789-1|issn=0002-9343}}</ref>

In a retrospective study, 72% of women with [[fibromyalgia]] reported a worsening of symptoms just before their periods.<ref>{{Cite journal|last=Østensen|first=Monika|last2=Rugelsjoen|first2=Anne|last3=Wigers|first3=Sigrid Horven|date=1997-01-01|title=The Effect of Reproductive Events and Alterations of Sex Hormone Levels on the Symptoms of Fibromyalgia|url=https://doi.org/10.3109/03009749709065698|journal=Scandinavian Journal of Rheumatology|volume=26|issue=5|pages=355–360|doi=10.3109/03009749709065698|issn=0300-9742|pmid=9385346}}</ref>

Women with these diseases may experiencing a worsening of symptoms at specific points in their menstrual cycle, particularly just before or around their periods.<ref>{{Cite journal|last=Zierau|first=Oliver|date=2012|title=Role of female sex hormones, estradiol and progesterone, in mast cell behavior|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377947/|journal=Front Immunol|volume=|pages=|via=}}</ref>

== Managing premenstrual symptoms ==

[[Nonsteroidal anti-inflammatory agents]] are occasionally effective in women with menstrual migraine, as are [[beta blockers]], [[calcium channel blocker]]s, [[ergotamine]], [[Antidepressant|antidepressant]]s, [[estrogen]] and [[estradiol]].<ref name=":2" />

== Pathophysiology of menstrual symptoms ==

[[Estrogen]] may directly affect [[blood vessel]]s by stimulating [[nitric oxide]] release. Women with a history of menstrual migraine had a heightened activation of the [[nitro oxide]] and [[L-arginine]] pathways, especially during the luteal phase.<ref>{{Cite journal|last=Brandes|first=Jan Lewis|date=2006-04-19|title=The Influence of Estrogen on Migraine: A Systematic Review|url=https://jamanetwork.com/journals/jama/fullarticle/202685|journal=JAMA|language=en|volume=295|issue=15|pages=1824–1830|doi=10.1001/jama.295.15.1824|issn=0098-7484}}</ref>

== Notable studies ==
* 2011, Gynecological History in Chronic Fatigue Syndrome: A Population-Based Case-Control Study<ref>{{Cite journal|last=Boneva|first=Roumiana S.|last2=Maloney|first2=Elizabeth M.|last3=Lin|first3=Jin-Mann|last4=Jones|first4=James F.|last5=Wieser|first5=Friedrich|last6=Nater|first6=Urs M.|last7=Heim|first7=Christine M.|last8=Reeves|first8=William C.|date=Jan 2011|title=Gynecological history in chronic fatigue syndrome: a population-based case-control study|url=https://www.ncbi.nlm.nih.gov/pubmed/21091051|journal=Journal of Women's Health (2002)|volume=20|issue=1|pages=21–28|doi=10.1089/jwh.2009.1900|issn=1931-843X|pmc=3017420|pmid=21091051|quote=|author-link=|author-link2=|author-link3=Jin-Mann Sally Lin|author-link4=|author-link5=|via=|author-link8=William Reeves}}</ref>

== See also ==

*[[Pregnancy]]
*[[Premenstrual syndrome]]

== References ==
<references />

[[Category:Triggers and risk factors]]

Progesterone

2019-08-09T06:25:23Z

Mbunke:

Progesterone is a steroid and sex hormone that is created endogenously (by our own bodies) in the female reproduction organs, adrenal glands, adipose tissue, and nervous tissue, especially the brain. It is the primary hormone in the steroid class ''progestogens''. Although widely known to play a large role in the menstrual cycle and pregnancy, scientists are just beginning to understand the enormous range of effects progesterone can have on the human body and its many systems. The word progesterone comes from the Latin ''pro-'', meaning "for," and ''gest-'', referring to pregnancy (as in "gestation"). It is commonly called the "pregnancy hormone."

=== Progesterone vs. Progestins ===
''Progestins'' are a synthetic form of progesterone that differ in molecular makeup from the progesterone created by our bodies. Progestins are used by pharmaceutical companies in medications and contraceptives. They are purposefully created to differ in structure from progesterone for patenting purposes (it is often not possible to patent a chemical as it exists in nature) and in order to create desired side-effects such as those that prevent pregnancy from occurring. There are around 10 different progestins used in contraceptive pills.

Women that take progestins should be aware that these hormones do not perfectly mimic natural progesterone, because they can cause unwanted side-effects, ranging in severity from acne to breast cancer.<ref>{{Cite journal|last=Gebel Berg|first=Erika|date=2015-03-25|title=The Chemistry of the Pill|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827491/|journal=ACS Central Science|volume=1|issue=1|pages=5–7|doi=10.1021/acscentsci.5b00066|issn=2374-7943|pmc=4827491|pmid=27162937}}</ref><ref>{{Cite journal|last=Santen|first=Richard J|date=2003-11-01|title=Risk of breast cancer with progestins: critical assessment of current data|url=http://www.sciencedirect.com/science/article/pii/S0039128X03001387|journal=Steroids|series=The 2nd International Symposium on Progestins, Progesterone Receptor Modulators and Progesterone Antagonists|volume=68|issue=10|pages=953–964|doi=10.1016/S0039-128X(03)00138-7|issn=0039-128X}}</ref>

==Bio-Identical Progesterone & BHRT ==
Many functional medicine doctors have begun supplementing patients with imbalanced hormone levels with bio-identical hormone replacement therapy (BHRT). The term "bio-identical" distinguishes these hormone supplements from the more conventionally used synthetic hormones created by pharmaceutical companies, because unlike the latter, bio-identical hormone supplements are identical in molecular structure to the natural hormones our bodies create. Whereas hormone replacement therapy (HRT) is widely known and highly conventional among mainstream medicine, BHRT is most often only heard of in functional or integrative medicine. A practitioner who uses BHRT will likely measure your hormone levels via saliva or blood sample, and prescribe your hormones through a compounding pharmacy.

Bio-identical progesterone is synthesized from the naturally occurring diosgenin in wild yams or from the stigmasterol found in soy beans and can be taken as a transdermal cream, pill, or vaginal gel.<ref>{{Cite web|url=https://www.health.harvard.edu/womens-health/what-are-bioidentical-hormones|title=What are bioidentical hormones?|last=Publishing|first=Harvard Health|website=Harvard Health|access-date=2019-08-08}}</ref><ref>{{Cite web|url=http://pennstatehershey.adam.com/content.aspx?productId=107&pid=33&gid=000280|title=Complementary and Alternative Medicine - Penn State Hershey Medical Center - Wild yam - Penn State Hershey Medical Center|website=pennstatehershey.adam.com|access-date=2019-08-08}}</ref><ref>{{Cite web|url=https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/stigmasterol|title=Stigmasterol - an overview {{!}} ScienceDirect Topics|website=www.sciencedirect.com|access-date=2019-08-08}}</ref> Over-the-counter progesterone supplements exist, but are likely too weak to be effective, and therefore a prescription is needed.

Although bio-identical progesterone is sometimes considered more "natural" than progestins because its molecular structure is identical to endogenous progesterone, both progestins and bio-identical progesterone are synthesized by humans. Many believe bio-identical progesterone to be safe, but more long-term research studies are needed to confirm this.

== Role in the Menstrual Cycle ==

=== Cycle Overview ===

==== Follicular Phase ====
At the beginning of a woman's cycle, the hypothalamus begins to secrete Gonadotropin Releasing Hormone (GnRH), stimulating the pituitary to create Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH), which travel to the ovaries. FSH causes follicles in the ovaries to begin to mature. Several follicles, each of which stores an egg, begin to grow as they mature, and in the process release estrogen. This estrogen produces a negative feedback during the first 10 days of the cycle that tells to the pituitary to inhibit the release of LH. It is important to note that ''low'' levels of estrogen will inhibit the release of LH from the pituitary, while ''high'' levels will stimulate it.

==== Ovulation ====
As estrogen continues to rise due to the maturing follicles, it also causes FSH levels to fall steadily (''low'' estrogen levels trigger the release of FSH). Around day 10 of the cycle, estrogen levels reach a threshold which stops the negative feedback of LH and begins a positive one resulting in the secretion of LH by the pituitary. The resulting spike in LH triggers the most mature follicle to release an egg (or oocyte); this is called ovulation.

==== Luteal Phase ====
After ovulation, the empty follicle will begin to die. This dying follicle is called a corpus luteum. As the corpus luteum degrades, it secretes three hormones: estrogen, inhibin, and progesterone. Inhibin provides a negative feedback to the pituitary to suppress the production of FSH. Progesterone provides a similar feedback to prohibit the release of GnRH, which in turn decreases the levels of LH and FSH. It also stimulates endometrial growth (the interior lining of the uterus).

As the corpus luteum degenerates, it will secrete fewer and fewer hormones, and progesterone, estrogen, and inhibin will steadily decrease. In the absence of fertilization, the decreasing levels of progesterone can no longer maintain the lining of the uterine wall, so the wall dies and sheds out of the body, resulting in menstruation. This decrease in progesterone also allows for the secretion of GnRH to begin again, and the cycle repeats.

Progesterone only exists in high levels during the second half of the menstrual cycle, the Luteal Phase.<ref>{{Cite journal|last=Reed|first=Beverly G.|last2=Carr|first2=Bruce R.|date=2000|editor-last=Feingold|editor-first=Kenneth R.|editor2-last=Anawalt|editor2-first=Bradley|editor3-last=Boyce|editor3-first=Alison|editor4-last=Chrousos|editor4-first=George|editor5-last=Dungan|editor5-first=Kathleen|editor6-last=Grossman|editor6-first=Ashley|editor7-last=Hershman|editor7-first=Jerome M.|editor8-last=Kaltsas|editor8-first=Gregory|editor9-last=Koch|editor9-first=Christian|title=The Normal Menstrual Cycle and the Control of Ovulation|url=http://www.ncbi.nlm.nih.gov/books/NBK279054/|location=South Dartmouth (MA)|publisher=MDText.com, Inc.|pmid=25905282}}</ref> In the absence of fertilization, the corpus luteum will last for 11 to 17 days; it is during these days a woman can expect progesterone levels to be highest.

===Exogenous Progesterone, Preventing Ovulation, and Contraceptives ===
Many contraceptives use [[progestins]] (synthetic progesterone) to prevent ovulation. They can also prevent pregnancy by thickening the cervical mucus, which blocks sperm from entering the uterus, and thinning the lining of the uterine wall, which prevents implantation of a fertilized egg (although endogenous progesterone helps to ''thicken'' this lining, the slightly different structure of some progestins results in the opposite effect). The most common form of birth control, combined oral contraceptive pills, also simply called "The Pill," uses progestins and estrogen to prevent pregnancy.

====How Progestins & Progesterone Prevent Ovulation ====
The chemical process by which progesterone and progestins prevent ovulation centers around their ability in the Follicular Phase to stop the release of Luteinizing Hormone (LH) by the anterior pituitary. Progesterone/progestins naturally create a negative feedback to the Hypothalamus, causing the latter to inhibit the release of Gonadotropin Releasing Hormone (GnRH). Without enough GnRH to stimulate the release of LH from the pituitary, LH levels will not spike as they usually do around day 13-14 in the cycle, and ovulation will not occur.

==== Endogenous Progesterone Levels in Luteal Phase when Ovulation Fails ====
This failure to ovulates means no follicle will release an egg and degrade into a corpus luteum. The corpus luteum (CL), or dying follicle, is the main source of endogenous progesterone in the female cycle, therefore without the CL, endogenous progesterone levels will remain low during the second half of the cycle. Women taking either progestins or exogenous bio-identical progesterone at certain levels should be aware that this process halting the production of endogenous progesterone may be taking place, especially for those trying to conceive and because this hormone plays an important role not only in reproduction, but in the brain as well (see "[[Progesterone in the Brain]]" below).

There is currently no research suggesting universally "safe" levels of exogenous bio-identical progesterone doses that will not prevent ovulation from occurring. The hormone feedback loops that are integral to the female cycle are incredibly complex and sensitive, and exogenous progesterone is metabolized at different rates in different females. These factors make ovulation-safe levels very difficult to predict.

== Reference Ranges ==
Reference ranges vary slightly by lab; the following is an example of reference ranges for progesterone levels in blood serum used by the Mayo Clinic:<ref>{{Cite web|url=https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/8141|title=PGSN - Clinical: Progesterone, Serum|website=www.mayocliniclabs.com|access-date=2019-08-08}}</ref>
{| class="wikitable"
! colspan="5" |Progesterone Reference Ranges (ng/mL)*
|-
| rowspan="5" |Males
|< 4 weeks
| colspan="3" |not established
|-
|4 weeks - < 12 mos.
| colspan="3" |< or = 0.66
|-
|12 mos. - 9 yrs.
| colspan="3" |< or = 0.35
|-
|10 - 17 yrs.
| colspan="3" |< or = 0.5
|-
|> or = 18 yrs.
| colspan="3" |< 0.20
|-
| rowspan="10" |Females
| rowspan="3" |Pre-pubescent
|< 4 days
| colspan="2" |not established
|-
|4 days - < 12 mos.
| colspan="2" |< or = 1.3
|-
|12 mos. - 9 yrs.
| colspan="2" |< or = 0.35
|-
| rowspan="7" |Adult
| rowspan="3" |> or = 18 yrs.
|Follicular phase
|< or = 0.89
|-
|Ovulation
|< or = 12
|-
|Luteal phase
|1.8 - 24
|-
| rowspan="3" |Pregnancy
|1st trimester
|11-44
|-
|2nd trimester
|25-83
|-
|3rd trimester
|58-214
|-
|Post-menopausal
| colspan="2" |< or = 0.20
|}
''*Reference intervals are based on central 90% of healthy population''

==Progesterone & Estrogen: A Balancing Act ==
One of the reasons it is difficult to measure the effects of progesterone and estrogen is that these two primary female sex hormones work in concert with each other, and it is therefore often the case that their ''ratio'' is more important than their independent levels. Many of the functions of estrogens are countered by progesterone including tissue growth, inflammation, immune function, and uterine muscle contraction. When progesterone does not exist in sufficient levels in the body, it results in "estrogen dominance," which can lead to breast cancer, endometriosis, and other pathologies.<ref>{{Cite journal|last=Clemons|first=Mark|last2=Goss|first2=Paul|date=2001-01-25|title=Estrogen and the Risk of Breast Cancer|url=https://doi.org/10.1056/NEJM200101253440407|journal=New England Journal of Medicine|volume=344|issue=4|pages=276–285|doi=10.1056/NEJM200101253440407|issn=0028-4793|pmid=11172156}}</ref><ref>{{Cite web|url=https://profile.thieme.de/HTML/sso/ejournals/login.htm?rdeLocaleAttr=en&type=default&subsidiary=www.thieme-connect.com&hook_url=https%3A%2F%2Fwww.thieme-connect.com%2Fproducts%2Fejournals%2Fhtml%2F10.1055%2Fs-0034-1376355|title=Thieme - Login|website=profile.thieme.de|doi=10.1055/s-0034-1376355|access-date=2019-08-09}}</ref> It is in establishing the correct levels of ''both'' estrogens and progesterone that a healthy homeostasis is achieved and the pathogenesis of endometriosis, infertility, cancer, and more can be diminished.

{| class="wikitable"
|+Estrogen's Functions & Progesterone's Counter-Functions
|'''Estrogen'''
|'''Progesterone'''
|-
|Stimulates tissue growth
|Stops tissue growth, promotes cell death
|-
|Stimulates contraction of uterine muscles
|Decreases uterine muscle contractions, promotes uterine muscle relaxation
|-
|Promotes edema (fluid-retention)
|Decreases edema
|-
|Most often promotes inflammation
|Most often anti-inflammatory, suppresses pro-inflammatory cytokines
|-
|Promotes immune activation (influx of neutrophils and activation of macrophages)
|Immunosuppressant, promotes immunotolerance
|}

=== Inflammation ===
Although estrogen has some anti-inflammatory effects, it most often functions as a pro-inflammatory hormone. Progesterone, on the other hand, which often down-regulates estrogen-mediated actions, functions as a powerful anti-inflammatory steroid. Both are critical in maintaining a normal menstrual cycle and healthy pregnancies. Estrogen's inflammatory effects in the absence of progesterone's anti-inflammatory actions are necessary for stimulating the shedding of the uterine wall in menstruation, and some scientists even describe menstruation itself as an "acute inflammatory response of ESCs [endometrial stromal cells] to progesterone withdrawal."<ref>{{Cite web|url=https://profile.thieme.de/HTML/sso/ejournals/login.htm?rdeLocaleAttr=en&type=default&subsidiary=www.thieme-connect.com&hook_url=https%3A%2F%2Fwww.thieme-connect.com%2Fproducts%2Fejournals%2Fhtml%2F10.1055%2Fs-0034-1376355|title=Thieme - Login|website=profile.thieme.de|doi=10.1055/s-0034-1376355#jr00900-120|access-date=2019-08-09}}</ref>

Progesterone's anti-inflammatory effect has also been found to aid in recovery from traumatic brain injury in rats, fight gingivitis in monkeys, and decrease signs of autoimmune encephalomyelitis (EAE) in mice.<ref>{{Cite journal|last=He|first=Jun|last2=Evans|first2=Chheng-Orn|last3=Hoffman|first3=Stuart W.|last4=Oyesiku|first4=Nelson M.|last5=Stein|first5=Donald G.|date=2004-10-01|title=Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury|url=http://www.sciencedirect.com/science/article/pii/S0014488604002390|journal=Experimental Neurology|volume=189|issue=2|pages=404–412|doi=10.1016/j.expneurol.2004.06.008|issn=0014-4886}}</ref><ref>{{Cite journal|last=Deasy|first=M. J.|last2=Grota|first2=L. J.|last3=Kennedy|first3=J. E.|date=1972|title=The effect of estrogen progesterone and cortisol on gingival inflammation|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0765.1972.tb00636.x|journal=Journal of Periodontal Research|language=en|volume=7|issue=2|pages=111–124|doi=10.1111/j.1600-0765.1972.tb00636.x|issn=1600-0765}}</ref><ref>{{Cite journal|last=Nicola|first=A. F. De|last2=Deniselle|first2=M. C. Gonzalez|last3=Garay|first3=L.|last4=Meyer|first4=M.|last5=Gargiulo‐Monachelli|first5=G.|last6=Guennoun|first6=R.|last7=Schumacher|first7=M.|last8=Carreras|first8=M. C.|last9=Poderoso|first9=J. J.|date=2013|title=Progesterone Protective Effects in Neurodegeneration and Neuroinflammation|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/jne.12043|journal=Journal of Neuroendocrinology|language=en|volume=25|issue=11|pages=1095–1103|doi=10.1111/jne.12043|issn=1365-2826}}</ref> It is known to suppress pro-inflammatory cytokines,<ref>{{Cite journal|last=Munoz-Suano|first=Alba|last2=Hamilton|first2=Alexander B.|last3=Betz|first3=Alexander G.|date=2011-04-13|title=Gimme shelter: the immune system during pregnancy|url=http://dx.doi.org/10.1111/j.1600-065x.2011.01002.x|journal=Immunological Reviews|volume=241|issue=1|pages=20–38|doi=10.1111/j.1600-065x.2011.01002.x|issn=0105-2896}}</ref> such as the inhibition [[IL-6]] and [[IL-8]] in the inflammatory response to [[lipopolysaccharides]] in human uterine cervical fibroblasts.<ref>http://www.sciencedirect.com/science/article/pii/S0024320512000136</ref>

It is unknown whether progesterone functions independently as an anti-inflammatory, or whether it must work in concert in estrogen to have this effect.

====Progesterone Resistance & Inflammation in Endometriosis ====
Endometriosis is a condition in which tissue grows not only on the internal walls of the uterus, but also on the ovaries, fallopian tubes, and external uterine walls, resulting in pain and sometimes infertility. Research suggests that the etiology of endometriosis centers around a disruption of estrogen-progesterone homeostasis in the uterus, caused by "progesterone resistance," which leads to increased inflammation.<ref>{{Cite web|url=https://profile.thieme.de/HTML/sso/ejournals/login.htm?rdeLocaleAttr=en&type=default&subsidiary=www.thieme-connect.com&hook_url=https%3A%2F%2Fwww.thieme-connect.com%2Fproducts%2Fejournals%2Fhtml%2F10.1055%2Fs-0034-1376355|title=Thieme - Login|website=profile.thieme.de|doi=10.1055/s-0034-1376355#jr00900-120|access-date=2019-08-09}}</ref> This progesterone resistance may lead to increased production of estrogen and pro-inflammatory cytokine presence including IL-1β, TNF-α, LIF, IL-6, IL-8, IL-11, NF-kB, p53, and STAT3. While these cytokines aid in embryonic implantation, levels that are too high or last too long can lead to aberrant outcomes like endometriosis. Through studying the effects of progesterone on endometriosis and other conditions related to estrogen-dominance, many researchers are optimistic about the development of future treatments.<ref>{{Cite web|url=https://profile.thieme.de/HTML/sso/ejournals/login.htm?rdeLocaleAttr=en&type=default&subsidiary=www.thieme-connect.com&hook_url=https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0034-1376355|title=Thieme - Login|website=profile.thieme.de|doi=10.1055/s-0034-1376355|access-date=2019-08-09}}</ref>

==== Understanding the Effects of Progesterone and Estrogens ====
Deciphering the roles of progesterone and estrogen is extremely difficult because both can have a wide range of effects. Both hormones can have pro- ''and'' anti-inflammatory functions, depending on the physiological circumstances. Both can also lead to one outcome at low levels and the opposite outcome at high levels (see negative/positive feedback in "[[Role in the Menstrual Cycle]]" above).

Progesterone and estrogen act on cells by binding to specific receptors. Progesterone binds to two main receptors: PR-A and PR-B. When binding to the latter, progesterone decreases inflammation and increases responsiveness to estrogen, while binding to the former has the inverse effect.

== Progesterone in the Brain ==

=== Progesterone as a Neurosteroid ===
Progesterone not only plays a major role in female reproduction, but has many other important roles in both males and females. One such role is as a powerful neurosteroid. Neurosteroids are steroids synthesized in the brain that regulate the excitability of neurons. It has been shown to be important in myelin repair in rodents in the sciatic nerve. In this study, the administration of progesterone to the site of brain lesions led to the regeneration of new myelin sheaths.<ref>{{Cite journal|last=Baulieu|first=E.|last2=Schumacher|first2=M.
|date=Oct 2000|title=Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination|url=https://www.ncbi.nlm.nih.gov/pubmed/11108866|journal=Steroids|volume=65|issue=10-11|pages=605–612|issn=0039-128X|pmid=11108866}}</ref> Neurosteroids can have powerful effects on both pain perception and inflammation, and research has suggested that female sex hormones like progesterone play a key role in modulating chronic pain.<ref>{{Cite journal|last=Kuba|first=Tzipora|last2=Quinones-Jenab|first2=Vanya|date=2005-08-15|title=The role of female gonadal hormones in behavioral sex differences in persistent and chronic pain: clinical versus preclinical studies|url=https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16023915|journal=Brain Research Bulletin|volume=66|issue=3|pages=179–188|doi=10.1016/j.brainresbull.2005.05.009|issn=0361-9230|pmid=16023915}}</ref><ref>{{Cite journal|last=Riley|first=Joseph|last2=Robinson|first2=Michael|last3=Wise|first3=Emily|last4=Myers|first4=Cynthia|last5=Fillingim|first5=Roger|date=Jan 1998|title=Sex differences in the perception of noxious experimental stimuli: a meta-analysis|url=http://insights.ovid.com/|journal=Pain|language=ENGLISH|volume=74|issue=2-3|pages=181–187|doi=10.1016/S0304-3959(97)00199-1|issn=0304-3959|pmid=9520232}}</ref> Progesterone has been shown in mice to prevent neurodegeneration, increase muscle strength, and enhance respiratory activity. The same study showed that progesterone blocked pro-inflammatory mediators, lessened Iba1+ microglial cells, and decreased symptoms of brain inflammation in mice. It also reduced the production of [[nitric oxide]] and [[TNF-α]].<ref>{{Cite journal|last=Nicola|first=A. F. De|last2=Deniselle|first2=M. C. Gonzalez|last3=Garay|first3=L.|last4=Meyer|first4=M.|last5=Gargiulo‐Monachelli|first5=G.|last6=Guennoun|first6=R.|last7=Schumacher|first7=M.|last8=Carreras|first8=M. C.|last9=Poderoso|first9=J. J.|date=2013|title=Progesterone Protective Effects in Neurodegeneration and Neuroinflammation|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/jne.12043|journal=Journal of Neuroendocrinology|language=en|volume=25|issue=11|pages=1095–1103|doi=10.1111/jne.12043|issn=1365-2826}}</ref> Progesterone is neuroprotective, anti-inflammatory, and promyelinating, and could present great benefits for neurological illnesses. However, other studies have shown higher progesterone levels predict worse outcomes for traumatic brain injury in human females.<ref>{{Cite journal|last=Wunderle|first=Kathryn|last2=Hoeger|first2=Kathleen M.|last3=Wasserman|first3=Erin|last4=Bazarian|first4=Jeffrey J.|date=2014|title=Menstrual Phase as Predictor of Outcome After Mild Traumatic Brain Injury in Women|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237582/|journal=The Journal of head trauma rehabilitation|volume=29|issue=5|pages=E1–E8|doi=10.1097/HTR.0000000000000006|issn=0885-9701|pmc=5237582|pmid=24220566}}</ref>

In the conclusion of a 2018 survey of literature related to neurosteroids, Del Río et. al. wrote the following:<blockquote>"The present review shows that fluctuations in steroid hormones, influenced by factors such as age and health status, have consequences at the level of CNS [central nervous system] and PNS [peripheral nervous system]. Utilizing both classical and non-classical pathways, neurosteroids participate in the physiological regulation of neurogenesis, neuronal survival, synaptic function, and myelin formation, thus influencing neuronal plasticity. Because of these effects, neurosteroids will have different modulatory actions, exerting control over mood, cognition, and behavior. Additionally, they have a neuroprotective role in relation to certain neurocognitive pathologies."<ref>{{Cite journal|last=Del Río|first=Juan Pablo|last2=Alliende|first2=María I.|last3=Molina|first3=Natalia|last4=Serrano|first4=Felipe G.|last5=Molina|first5=Santiago|last6=Vigil|first6=Pilar|date=2018-05-23|title=Steroid Hormones and Their Action in Women's Brains: The Importance of Hormonal Balance|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974145/|journal=Frontiers in Public Health|volume=6|doi=10.3389/fpubh.2018.00141|issn=2296-2565|pmc=5974145|pmid=29876339}}</ref></blockquote>

=== Pain Modulation ===
Neurosteroids have been found to affect the sensory nervous system in ways that may prevent central sensitization (the process by which the NS becomes heightened to pain perception), and therefore reduce chronic pain. Researchers believe that both the administration of synthetic neurosteroids and treatments that promote the genesis of endogenous neurosteroids like progesterone could hold great promise for future pain management therapies. The latter has proven successful in several animal studies measuring neuropathic, inflammatory, and post-surgical pain.<ref>{{Cite journal|last=Todorovic|first=Slobodan M.|last2=Jevtovic-Todorovic|first2=Vesna|last3=Covey|first3=Douglas F.|last4=Joksimovic|first4=Sonja L.|date=2018|title=Neurosteroids in Pain Management: A New Perspective on an Old Player|url=https://www.frontiersin.org/articles/10.3389/fphar.2018.01127/full|journal=Frontiers in Pharmacology|language=English|volume=9|doi=10.3389/fphar.2018.01127|issn=1663-9812}}</ref><ref>{{Cite journal|last=Kastrup|first=Y|last2=Hallbeck|first2=M|last3=Amandusson|first3=Å|last4=Hirata|first4=S|last5=Hermanson|first5=O|last6=Blomqvist|first6=A|date=1999-11-12|title=Progesterone receptor expression in the brainstem of the female rat|url=http://www.sciencedirect.com/science/article/pii/S0304394099007533|journal=Neuroscience Letters|volume=275|issue=2|pages=85–88|doi=10.1016/S0304-3940(99)00753-3|issn=0304-3940}}</ref>

In women with Hypermobile Type Ehlers Danlos Syndrome, about one-third report a worsening of symptoms around the time of their periods, when both estrogen and progesterone are low.

=== Autonomic Nervous System ===
Progesterone has been shown to bind to receptors in the brainstems of rats that modulate pain as well as those that regulate the autonomic nervous system (ANS), the part of the NS that controls unconscious processes like heart rate, breathing, and digestion.<ref>{{Cite journal|last=Kastrup|first=Y|last2=Hallbeck|first2=M|last3=Amandusson|first3=Å|last4=Hirata|first4=S|last5=Hermanson|first5=O|last6=Blomqvist|first6=A|date=1999-11-12|title=Progesterone receptor expression in the brainstem of the female rat|url=http://www.sciencedirect.com/science/article/pii/S0304394099007533|journal=Neuroscience Letters|volume=275|issue=2|pages=85–88|doi=10.1016/S0304-3940(99)00753-3|issn=0304-3940}}</ref> Research has also shown increased autonomic cardiac function in human females during the ovulation phase, when progesterone begins to rise rapidly.<ref>{{Cite journal|last=Little|first=Betsy Carter|last2=Zahn|first2=Theodore P.|date=1974|title=Changes in Mood and Autonomic Functioning During the Menstrual Cycle|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1469-8986.1974.tb01118.x|journal=Psychophysiology|language=en|volume=11|issue=5|pages=579–590|doi=10.1111/j.1469-8986.1974.tb01118.x|issn=1469-8986}}</ref> However, it is unknown whether this is a result of progesterone alone or progesterone combined with estrogen. The latter theory is supported by studies that have shown autonomic regulation of cardiac function suffers during the Luteal Phase and that estrogen is likely to play a stronger role in sympathetic cardiac balance than progesterone.<ref>{{Cite journal|last=Fuenmayor|first=Abdel J.|last2=Ramı́rez|first2=Leonardo|last3=Fuenmayor|first3=Abdel M.|date=2000-02-15|title=Left ventricular function and autonomic nervous system balance during two different stages of the menstrual cycle|url=http://www.sciencedirect.com/science/article/pii/S016752739900193X|journal=International Journal of Cardiology|volume=72|issue=3|pages=243–246|doi=10.1016/S0167-5273(99)00193-X|issn=0167-5273}}</ref><ref>{{Cite journal|last=Mercuro|first=Giuseppe|last2=Zoncu|first2=Sandra|last3=Saiu|first3=Francesca|last4=Mascia|first4=Monica|last5=Melis|first5=Gian Benedetto|last6=Rosano|first6=Giuseppe M. C.|date=2004-02-20|title=Menopause induced by oophorectomy reveals a role of ovarian estrogen on the maintenance of pressure homeostasis|url=https://www.ncbi.nlm.nih.gov/pubmed/14757272|journal=Maturitas|volume=47|issue=2|pages=131–138|issn=0378-5122|pmid=14757272}}</ref>

=== Mood ===
Progesterone is well-known to have a calming effect and promote feelings of "elation and vigor."<ref>{{Cite journal|last=Little|first=Betsy Carter|last2=Zahn|first2=Theodore P.|date=1974|title=Changes in Mood and Autonomic Functioning During the Menstrual Cycle|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1469-8986.1974.tb01118.x|journal=Psychophysiology|language=en|volume=11|issue=5|pages=579–590|doi=10.1111/j.1469-8986.1974.tb01118.x|issn=1469-8986}}</ref> Some medical experts believe low progesterone to estrogen ratios are often the source of anxiety disorders.

== Progesterone and Collagen ==
The existing medical literature presents conflicting data on the relationship between of female sex hormones and connective tissue, joint laxity and tendons. Much more research is needed, but we do know that these hormones are integral to changes in the tissues of the cervix, endometrium, and other parts of the female reproduction system, especially during pregnancy.<ref>{{Cite journal|last=Mahendroo|first=Mala|last2=Iozzo|first2=Renato|last3=Myers|first3=Kristin|last4=Akins|first4=Meredith|last5=Yoshida|first5=Kyoko|last6=Nallasamy|first6=Shanmugasundaram|date=2017-04-01|title=Steroid Hormones Are Key Modulators of Tissue Mechanical Function via Regulation of Collagen and Elastic Fibers|url=https://academic.oup.com/endo/article/158/4/950/2991885|journal=Endocrinology|language=en|volume=158|issue=4|pages=950–962|doi=10.1210/en.2016-1930|issn=0013-7227}}</ref><ref>{{Cite journal|last=Eeckhout|first=Y.|last2=Courtoy|first2=P. J.|last3=Donnez|first3=J.|last4=Marbaix|first4=E.|date=1992-12-15|title=Progesterone regulates the activity of collagenase and related gelatinases A and B in human endometrial explants|url=https://www.pnas.org/content/89/24/11789|journal=Proceedings of the National Academy of Sciences|language=en|volume=89|issue=24|pages=11789–11793|doi=10.1073/pnas.89.24.11789|issn=0027-8424|pmid=1465400}}</ref>

One study has shown progesterone had negative effect on ligament strength, measured by the higher likelihood of anterior cruciate ligament injury in female athletes following ovulation.<ref>{{Cite journal|last=Wojtys|first=Edward M.|last2=Huston|first2=Laura J.|last3=Lindenfeld|first3=Thomas N.|last4=Hewett|first4=Timothy E.|last5=Greenfield|first5=Mary Lou V. H.|date=1998-09-01|title=Association Between the Menstrual Cycle and Anterior Cruciate Ligament Injuries in Female Athletes|url=https://doi.org/10.1177/03635465980260050301|journal=The American Journal of Sports Medicine|language=en|volume=26|issue=5|pages=614–619|doi=10.1177/03635465980260050301|issn=0363-5465}}</ref> Other studies support this finding.<ref>{{Cite journal|last=Deie|first=Masataka|last2=Sakamaki|first2=Yukie|last3=Sumen|first3=Yoshio|last4=Urabe|first4=Yukio|last5=Ikuta|first5=Yoshikazu|date=2002-06-01|title=Anterior knee laxity in young women varies with their menstrual cycle|url=https://doi.org/10.1007/s00264-001-0326-0|journal=International Orthopaedics|language=en|volume=26|issue=3|pages=154–156|doi=10.1007/s00264-001-0326-0|issn=1432-5195|pmc=PMC3620888|pmid=12073107}}</ref> However, Miller et. al. have shown that "there is no effect of menstrual cycle phase, at rest or in response to an acute bout of exercise, on myofibrillar protein synthesis and muscle collagen synthesis in women."<ref>{{Cite journal|last=Miller|first=Benjamin F.|last2=Hansen|first2=Mette|last3=Olesen|first3=Jens L.|last4=Flyvbjerg|first4=Allan|last5=Schwarz|first5=Peter|last6=Babraj|first6=John A.|last7=Smith|first7=Kenneth|last8=Rennie|first8=Michael J.|last9=Kjaer|first9=Michael|date=2006-01-01|title=No effect of menstrual cycle on myofibrillar and connective tissue protein synthesis in contracting skeletal muscle|url=https://www.physiology.org/doi/full/10.1152/ajpendo.00300.2005|journal=American Journal of Physiology-Endocrinology and Metabolism|volume=290|issue=1|pages=E163–E168|doi=10.1152/ajpendo.00300.2005|issn=0193-1849}}</ref> There is evidence that combined oral contraceptives (containing both estradiol and progestins) have an "inhibiting effect on collagen synthesis in tendon, bone, and muscle connective tissue, which may be related to a lower bioavailability of IGF-I [insulin-like growth factor]."<ref>{{Cite journal|last=Hansen|first=M.|last2=Miller|first2=B. F.|last3=Holm|first3=L.|last4=Doessing|first4=S.|last5=Petersen|first5=S. G.|last6=Skovgaard|first6=D.|last7=Frystyk|first7=J.|last8=Flyvbjerg|first8=A.|last9=Koskinen|first9=S.|date=2009-04-01|title=Effect of administration of oral contraceptives in vivo on collagen synthesis in tendon and muscle connective tissue in young women|url=https://www.physiology.org/doi/full/10.1152/japplphysiol.90933.2008|journal=Journal of Applied Physiology|volume=106|issue=4|pages=1435–1443|doi=10.1152/japplphysiol.90933.2008|issn=8750-7587}}</ref> Estrogen and/or testosterone are believed to have a protective effect on collagen strength as skin ages.<ref>{{Cite journal|last=Cooper|first=D.|last2=Magos|first2=A.|last3=Darby|first3=A. J.|last4=Studd|first4=J. W.|last5=Moniz|first5=C. F.|last6=Brincat|first6=M.|date=1983-11-05|title=Sex hormones and skin collagen content in postmenopausal women.|url=https://www.bmj.com/content/287/6402/1337|journal=Br Med J (Clin Res Ed)|language=en|volume=287|issue=6402|pages=1337–1338|doi=10.1136/bmj.287.6402.1337|issn=0007-1447|pmid=6416400}}</ref>

The results of one analysis of 386 women with Hypermobility Type Ehlers Danlos Syndrome (hEDS), a connective tissue disorder, suggested that hEDS symptoms, including fatigue, improve with the administration of progestins. About one-third of the women reported a worsening of symptoms around menstruation (when both estrogen and progesterone are low).<ref>{{Cite journal|last=Hugon-Rodin|first=Justine|last2=Lebègue|first2=Géraldine|last3=Becourt|first3=Stéphanie|last4=Hamonet|first4=Claude|last5=Gompel|first5=Anne|date=2016-09-13|title=Gynecologic symptoms and the influence on reproductive life in 386 women with hypermobility type ehlers-danlos syndrome: a cohort study|url=https://doi.org/10.1186/s13023-016-0511-2|journal=Orphanet Journal of Rare Diseases|volume=11|issue=1|pages=124|doi=10.1186/s13023-016-0511-2|issn=1750-1172|pmc=PMC5020453|pmid=27619482}}</ref> The following two tables are from the aforementioned study:

==== Table - Gynecological Symptoms and Prevalence of Endometriosis<ref>{{Cite journal|last=Hugon-Rodin|first=Justine|last2=Lebègue|first2=Géraldine|last3=Becourt|first3=Stéphanie|last4=Hamonet|first4=Claude|last5=Gompel|first5=Anne|date=2016-09-13|title=Gynecologic symptoms and the influence on reproductive life in 386 women with hypermobility type ehlers-danlos syndrome: a cohort study|url=https://doi.org/10.1186/s13023-016-0511-2|journal=Orphanet Journal of Rare Diseases|volume=11|issue=1|pages=124|doi=10.1186/s13023-016-0511-2|issn=1750-1172|pmc=PMC5020453|pmid=27619482}}</ref> ====
{| class="wikitable"
!Symptoms
!''n'' (%)
|-
|Menorrhagia
|292 (76)
|-
|Metrorrhagia
|83 (22)
|-
|Dysmenorrhea
|278 (72)
|-
|Deep dyspareuniea
|118 (38)
|-
|Intromission dyspareuniea
|148 (43)
|-
|Endometriosis
|20 (6)
|}

==== Table - The influence of Hormones on hEDS Symptoms (hEDS Symptoms: Chronic Pain, Fatigue)<ref>{{Cite journal|last=Hugon-Rodin|first=Justine|last2=Lebègue|first2=Géraldine|last3=Becourt|first3=Stéphanie|last4=Hamonet|first4=Claude|last5=Gompel|first5=Anne|date=2016-09-13|title=Gynecologic symptoms and the influence on reproductive life in 386 women with hypermobility type ehlers-danlos syndrome: a cohort study|url=https://doi.org/10.1186/s13023-016-0511-2|journal=Orphanet Journal of Rare Diseases|volume=11|issue=1|pages=124|doi=10.1186/s13023-016-0511-2|issn=1750-1172|pmc=PMC5020453|pmid=27619482}}</ref> ====
{| class="wikitable"
!hEDS patients not influenced by menstruation ''n'' = 197 (%)
!hEDS patients influenced by menstruation ''n'' = 133 (%)
!''p''
|-
|Influenced by puberty
|85/197 (43.2)
|79/133 (58.7)
|-
| colspan="3" |'''Impact of CHC*'''
|-
|Worsened on CHC
|5/90 (5.6)
|15/58 (25.9)
|-
|Improved on CHC
|12/90 (13.3)
|9/58 (15.5)
|-
|Unchanged on CHC
|73/90 (81.1)
|34/58 (58.6)
|-
|Improved by menopause
|6/33 (18.2)
|3/17 (17.7)
|}
<nowiki>*</nowiki>Combined hormonal contraceptives (estrogen and progestins)

== See also ==

*[[Menstrual cycle]]
*[[Pregnancy]]

==References==
<references />
[[Category:Neurotransmitters and hormones]]
[[Category:Sex hormones]]
[[Category:Hormones]]

Progesterone

2019-08-09T02:53:27Z

Mbunke:added to progesterone in the brain

Progesterone is a steroid and sex hormone that is created endogenously (by our own bodies). It is the primary hormone in the steroid class ''progestogens''. Although widely known to play a large role in the menstrual cycle and pregnancy, scientists are just beginning to understand the enormous range of effects progesterone can have on the human body and its many systems. The word progesterone comes from the Latin ''pro-'', meaning "for," and ''gest-'', referring to pregnancy (as in "gestation"). It is commonly called the "pregnancy hormone."

=== Progesterone vs. Progestins ===
''Progestins'' are a synthetic form of progesterone that differ in molecular makeup from the progesterone created by our bodies. Progestins are used by pharmaceutical companies in medications and contraceptives. They are purposefully created to differ in structure from progesterone for patenting purposes (it is often not possible to patent a chemical as it exists in nature) and in order to create desired side-effects such as those that prevent pregnancy from occurring. There are around 10 different progestins used in contraceptive pills.

Women that take progestins should be aware that these hormones do not perfectly mimic natural progesterone, because they can cause unwanted side-effects, ranging in severity from acne to breast cancer.<ref>{{Cite journal|last=Gebel Berg|first=Erika|date=2015-03-25|title=The Chemistry of the Pill|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827491/|journal=ACS Central Science|volume=1|issue=1|pages=5–7|doi=10.1021/acscentsci.5b00066|issn=2374-7943|pmc=4827491|pmid=27162937}}</ref><ref>{{Cite journal|last=Santen|first=Richard J|date=2003-11-01|title=Risk of breast cancer with progestins: critical assessment of current data|url=http://www.sciencedirect.com/science/article/pii/S0039128X03001387|journal=Steroids|series=The 2nd International Symposium on Progestins, Progesterone Receptor Modulators and Progesterone Antagonists|volume=68|issue=10|pages=953–964|doi=10.1016/S0039-128X(03)00138-7|issn=0039-128X}}</ref>

==Bio-Identical Progesterone & BHRT ==
Many functional medicine doctors have begun supplementing imbalanced hormone levels with bio-identical hormone replacement therapy (BHRT). The term bio-identical distinguishes these hormone supplements from the often used synthetic derivatives created by pharmaceutical companies. The use of the latter is widely known and highly conventional among mainstream medicine, whereas BHRT is most often only heard of in functional or integrative medicine. Bio-identical hormone supplements are identical in molecular structure to the natural hormones your body creates. A practitioner who uses BHRT will likely measure your hormone levels via saliva or blood sample, and prescribe your hormones through a compounding pharmacy. Bio-identical progesterone is synthesized from the naturally occurring diosgenin in wild yams or from the stigmasterol found in soy beans and can be taken as a transdermal cream, pill, or vaginal gel.<ref>{{Cite web|url=https://www.health.harvard.edu/womens-health/what-are-bioidentical-hormones|title=What are bioidentical hormones?|last=Publishing|first=Harvard Health|website=Harvard Health|access-date=2019-08-08}}</ref><ref>{{Cite web|url=http://pennstatehershey.adam.com/content.aspx?productId=107&pid=33&gid=000280|title=Complementary and Alternative Medicine - Penn State Hershey Medical Center - Wild yam - Penn State Hershey Medical Center|website=pennstatehershey.adam.com|access-date=2019-08-08}}</ref><ref>{{Cite web|url=https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/stigmasterol|title=Stigmasterol - an overview {{!}} ScienceDirect Topics|website=www.sciencedirect.com|access-date=2019-08-08}}</ref>

Although bio-identical progesterone is sometimes considered more "natural" than progestins because its molecular structure is identical to the progesterone created by our bodies, both progestins and bio-identical progesterone are synthesized by humans. Many believe bio-identical progesterone to be safe, but more research is needed to confirm the long-term side effects.

== Role in the Menstrual Cycle ==

=== Cycle Overview ===
At the beginning of a woman's cycle, the hypothalamus begins to secrete Gonadotropin Releasing Hormone (GnRH), stimulating the pituitary to create Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH), which travel to the ovaries. FSH causes the ovaries to stimulate the maturation process of follicles. Several follicles, each of which stores an egg, begin to grow as they mature, and in the process releasing estrogen. This estrogen produces a negative feedback during the first 10 days of the cycle that tells to the pituitary to inhibit the release of LH. It is important to note that ''low'' levels of estrogen will inhibit the release of LH from the pituitary, while ''high'' levels will stimulate it.

As estrogen continues to rise due to the maturing follicles, is also causes FSH levels to fall steadily (low estrogen triggers the release of FSH). Around day 10 of the cycle, estrogen levels reach a threshold which stops the negative feedback loop and begins a positive one resulting in the secretion of LH by the pituitary. The resulting spike in LH triggers the most mature follicle to release an egg (or oocyte); this is known as ovulation.

After ovulation, the empty follicle will begin to die. This dying follicle is called a corpus luteum. As the corpus luteum degrades, it secretes estrogen, inhibin, and progesterone. Inhibin provides a negative feedback to the pituitary to suppress the production of FSH. Progesterone provides a similar feedback to prohibit the release of GnRH, which in turn decreases the levels of LH and FSH. It also stimulates endometrial growth (the lining of the uterus).

As the corpus luteum degenerates, it will secrete fewer and fewer hormones, and progesterone, estrogen, and inhibin will steadily decrease. This decrease in progesterone allows for the secretion of GnRH to begin again, and the cycle repeats again, unless the egg becomes fertilized. If the egg is not fertilized, the decreasing levels of progesterone can no longer maintain the lining of the uterine wall, so the wall dies and sheds out of the body, resulting in menstruation.

Progesterone only exists in high levels during the second half of the menstrual cycle, the Luteal Phase.<ref>{{Cite journal|last=Reed|first=Beverly G.|last2=Carr|first2=Bruce R.|date=2000|editor-last=Feingold|editor-first=Kenneth R.|editor2-last=Anawalt|editor2-first=Bradley|editor3-last=Boyce|editor3-first=Alison|editor4-last=Chrousos|editor4-first=George|editor5-last=Dungan|editor5-first=Kathleen|editor6-last=Grossman|editor6-first=Ashley|editor7-last=Hershman|editor7-first=Jerome M.|editor8-last=Kaltsas|editor8-first=Gregory|editor9-last=Koch|editor9-first=Christian|title=The Normal Menstrual Cycle and the Control of Ovulation|url=http://www.ncbi.nlm.nih.gov/books/NBK279054/|location=South Dartmouth (MA)|publisher=MDText.com, Inc.|pmid=25905282}}</ref> In the absence of fertilization, the corpus luteum will last for 11 to 17 days; it is during these days a woman can expect her progesterone levels to be highest.

===Exogenous Progesterone, Preventing Ovulation, and Contraceptives ===
Many contraceptives use progestins (synthetic progesterone) to prevent ovulation. They can also prevent pregnancy by thickening the cervical mucus, which blocks sperm from entering the uterus, and thinning the lining of the uterine wall, which prevents implantation of a fertilized egg (although endogenous progesterone helps to ''thicken'' this lining, the slightly different structure of some progestins results in the opposite effect). The most common form of birth control, combined oral contraceptive pills, also simply called "The Pill," uses progestins and estrogen to prevent pregnancy.

==== How Progestins & Progesterone Prevent Ovulation ====
The chemical process by which progesterone and progestins prevent ovulation centers around their ability to stop the release of Luteinizing Hormone (LH) by the anterior pituitary. Progesterone/progestins naturally create a negative feedback to the Hypothalamus, causing the latter to inhibit the release of Gonadotropin Releasing Hormone (GnRH). Without enough GnRH to stimulate the release of LH from the pituitary, LH levels will not spike as they usually around day 13-14 in the cycle, and ovulation will not occur.

==== Endogenous Progesterone Levels in Luteal Phase when Ovulation Fails ====
This failure to ovulates means no follicle will release an egg and degrade into a corpus luteum. The corpus luteum (CL), or dying follicle, is the main source of endogenous progesterone in the female cycle, therefore without the CL, endogenous progesterone levels will remain low during the second half of the cycle. Women taking either progestins or exogenous bio-identical progesterone at certain levels should be aware of this process halting the production of endogenous progesterone may be taking place, especially for those trying to conceive and because this hormone plays an important role not only in reproduction, but in the brain as well (see "[[Progesterone in the Brain]]" below).

There is currently no research suggesting universally "safe" levels of exogenous bio-identical progesterone doses that will not prevent ovulation from occurring. The hormone feedback loops that are integral to the female cycle are incredibly complex and sensitive, and exogenous progesterone is metabolized at different rates in different females. These factors make ovulation-safe levels very difficult to predict.

== Reference Ranges ==
Reference ranges vary slightly by lab; the following is an example of reference ranges for progesterone levels in blood serum used by the Mayo Clinic:<ref>{{Cite web|url=https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/8141|title=PGSN - Clinical: Progesterone, Serum|website=www.mayocliniclabs.com|access-date=2019-08-08}}</ref>
{| class="wikitable"
! colspan="5" |Progesterone Reference Ranges (ng/mL)*
|-
| rowspan="5" |Males
|< 4 weeks
| colspan="3" |not established
|-
|4 weeks - < 12 mos.
| colspan="3" |< or = 0.66
|-
|12 mos. - 9 yrs.
| colspan="3" |< or = 0.35
|-
|10 - 17 yrs.
| colspan="3" |< or = 0.5
|-
|> or = 18 yrs.
| colspan="3" |< 0.20
|-
| rowspan="10" |Females
| rowspan="3" |Pre-pubescent
|< 4 days
| colspan="2" |not established
|-
|4 days - < 12 mos.
| colspan="2" |< or = 1.3
|-
|12 mos. - 9 yrs.
| colspan="2" |< or = 0.35
|-
| rowspan="7" |Adult
| rowspan="3" |> or = 18 yrs.
|Follicular phase
|< or = 0.89
|-
|Ovulation
|< or = 12
|-
|Luteal phase
|1.8 - 24
|-
| rowspan="3" |Pregnancy
|1st trimester
|11-44
|-
|2nd trimester
|25-83
|-
|3rd trimester
|58-214
|-
|Post-menopausal
| colspan="2" |< or = 0.20
|}
''*Reference intervals are based on central 90th% of healthy population''

==Progesterone & Estrogen: A Balancing Act ==
One of the reasons it is difficult to measure the effects of progesterone and estrogen is that these two primary female sex hormones work in concert with each other, and it is their therefore often the case that their ''ratio'' is more important than their independent levels in the body. Many of the functions of estrogens are countered by progesterone including tissue and bone growth, inflammation, immune function, and uterine muscle contraction. When progesterone does not exist in sufficient levels in the body, it results in "estrogen dominance," which can lead to breast cancer, endometriosis, and other pathologies It is in establishing the correct levels of ''both'' estrogens and progesterone that a healthy homeostasis is achieved and the pathogenesis of endometriosis, infertility, cancer, and more can be diminished.

{| class="wikitable"
|+Estrogen's Functions & Progesterone's Counter-functions
|'''Estrogen'''
|'''Progesterone'''
|-
|Stimulates tissue growth
|Stops tissue growth, promotes cell death
|-
|Decreases the rate of bone breakdown
|Stimulates bone osteoblasts
|-
|Stimulates contraction of uterine muscles
|Decreases uterine muscle contractions, promotes uterine muscle relaxation
|-
|Promotes edema (fluid-retention)
|Decreases edema
|-
|Most often promotes inflammation
|Most often anti-inflammatory, suppresses pro-inflammatory cytokines
|-
|Promotes immune activation (influx of neutrophils and activation of macrophages)
|Immunosuppressant, promotes immunotolerance
|}

=== Inflammation ===
Although estrogen has some anti-inflammatory effects, it most often functions as a pro-inflammatory hormone. Progesterone, on the other hand, which often down-regulates estrogen-mediated actions, functions as a powerful anti-inflammatory steroid. Both are critical in maintaining a normal menstrual cycle and healthy pregnancies. Estrogen's inflammatory effects in the absence of progesterone's anti-inflammatory action are necessary for stimulating the shedding of the uterine wall in menstruation, and some scientists even describe menstruation itself as an "acute inflammatory response of ESCs [endometrial stromal cells] to progesterone withdrawal."<ref>{{Cite web|url=https://profile.thieme.de/HTML/sso/ejournals/login.htm?rdeLocaleAttr=en&type=default&subsidiary=www.thieme-connect.com&hook_url=https%3A%2F%2Fwww.thieme-connect.com%2Fproducts%2Fejournals%2Fhtml%2F10.1055%2Fs-0034-1376355|title=Thieme - Login|website=profile.thieme.de|doi=10.1055/s-0034-1376355#jr00900-120|access-date=2019-08-09}}</ref>

Progesterone's anti-inflammatory effect has also been found to aid in recovery from traumatic brain injury in rats, fight gingivitis in monkeys, and decrease signs of autoimmune encephalomyelitis (EAE) in mice.<ref>{{Cite journal|last=He|first=Jun|last2=Evans|first2=Chheng-Orn|last3=Hoffman|first3=Stuart W.|last4=Oyesiku|first4=Nelson M.|last5=Stein|first5=Donald G.|date=2004-10-01|title=Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury|url=http://www.sciencedirect.com/science/article/pii/S0014488604002390|journal=Experimental Neurology|volume=189|issue=2|pages=404–412|doi=10.1016/j.expneurol.2004.06.008|issn=0014-4886}}</ref><ref>{{Cite journal|last=Deasy|first=M. J.|last2=Grota|first2=L. J.|last3=Kennedy|first3=J. E.|date=1972|title=The effect of estrogen progesterone and cortisol on gingival inflammation|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0765.1972.tb00636.x|journal=Journal of Periodontal Research|language=en|volume=7|issue=2|pages=111–124|doi=10.1111/j.1600-0765.1972.tb00636.x|issn=1600-0765}}</ref><ref>{{Cite journal|last=Nicola|first=A. F. De|last2=Deniselle|first2=M. C. Gonzalez|last3=Garay|first3=L.|last4=Meyer|first4=M.|last5=Gargiulo‐Monachelli|first5=G.|last6=Guennoun|first6=R.|last7=Schumacher|first7=M.|last8=Carreras|first8=M. C.|last9=Poderoso|first9=J. J.|date=2013|title=Progesterone Protective Effects in Neurodegeneration and Neuroinflammation|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/jne.12043|journal=Journal of Neuroendocrinology|language=en|volume=25|issue=11|pages=1095–1103|doi=10.1111/jne.12043|issn=1365-2826}}</ref> It is known to suppress pro-inflammatory cytokines,<ref>{{Cite journal|last=Munoz-Suano|first=Alba|last2=Hamilton|first2=Alexander B.|last3=Betz|first3=Alexander G.|date=2011-04-13|title=Gimme shelter: the immune system during pregnancy|url=http://dx.doi.org/10.1111/j.1600-065x.2011.01002.x|journal=Immunological Reviews|volume=241|issue=1|pages=20–38|doi=10.1111/j.1600-065x.2011.01002.x|issn=0105-2896}}</ref> such as the inhibition [[IL-6]] and [[IL-8]] in the inflammatory response to [[lipopolysaccharides]] in human uterine cervical fibroblasts.<ref>http://www.sciencedirect.com/science/article/pii/S0024320512000136</ref>

It is unknown whether progesterone functions independently as an anti-inflammatory, or whether it must work in concert in estrogen to have this effect.

==== Progesterone Resistance & Inflammation in Endometriosis ====
Endometriosis is a condition in which tissue grows not only on the internal walls of the uterus, on the ovaries, fallopian tubes, and external uterine walls as well. It leads to pain and sometimes infertility. Research suggests that the etiology of endometriosis centers heavily on a disruption of estrogen-progesterone homeostasis in the uterus, caused by "progesterone resistance," which therefore leads to increased inflammation.<ref>{{Cite web|url=https://profile.thieme.de/HTML/sso/ejournals/login.htm?rdeLocaleAttr=en&type=default&subsidiary=www.thieme-connect.com&hook_url=https%3A%2F%2Fwww.thieme-connect.com%2Fproducts%2Fejournals%2Fhtml%2F10.1055%2Fs-0034-1376355|title=Thieme - Login|website=profile.thieme.de|doi=10.1055/s-0034-1376355#jr00900-120|access-date=2019-08-09}}</ref> This progesterone resistance may lead to increased production of estrogen and increased pro-inflammatory cytokine presence including IL-1β, TNF-α, LIF, IL-6, IL-8, IL-11, NF-kB, p53, and STAT3. While these cytokines aid in embryonic implantation, levels that are too high or last too long can lead to aberrant outcomes like endometriosis. Through studying the effects of progesterone on endometriosis and other conditions related to estrogen-dominance, many researchers are optimistic about the development of future treatment.<ref>{{Cite web|url=https://profile.thieme.de/HTML/sso/ejournals/login.htm?rdeLocaleAttr=en&type=default&subsidiary=www.thieme-connect.com&hook_url=https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0034-1376355|title=Thieme - Login|website=profile.thieme.de|doi=10.1055/s-0034-1376355|access-date=2019-08-09}}</ref>

==== Pro-inflammatory vs. Anti-inflammatory Effects ====
Deciphering the roles of progesterone and estrogen is extremely difficult because both can have a wide range of effects. Both hormones can have pro- ''and'' anti-inflammatory functions, depending on the physiological circumstances. Progesterone and estrogen act on cells by binding to specific receptors. Progesterone binds to two main receptors: PR-A and PR-B. When binding to the latter receptor, progesterone decreases inflammation and increases responsiveness to estrogen, while binding to the former has the converse effect.

== Progesterone in the Brain ==

=== Progesterone as a Neurosteroid ===
Progesterone not only plays a major role in female reproduction, but has many other important roles in both males and females. One such role is as a powerful neurosteroid. Neurosteroids are steroids synthesized in the brain that regulate the excitability of neurons. It has been shown to be important in myelin repair in rodents in the sciatic nerve. In one study, the administration of progesterone to the site of brain lesions led to the regeneration of new myelin sheaths.<ref>{{Cite journal|last=Baulieu|first=E.|last2=Schumacher|first2=M.
|date=Oct 2000|title=Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination|url=https://www.ncbi.nlm.nih.gov/pubmed/11108866|journal=Steroids|volume=65|issue=10-11|pages=605–612|issn=0039-128X|pmid=11108866}}</ref> Neurosteroids can have powerful effects on both pain perception and inflammation, and research has suggested that female sex hormones like progesterone play a key role in modulating chronic pain.<ref>{{Cite journal|last=Kuba|first=Tzipora|last2=Quinones-Jenab|first2=Vanya|date=2005-08-15|title=The role of female gonadal hormones in behavioral sex differences in persistent and chronic pain: clinical versus preclinical studies|url=https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16023915|journal=Brain Research Bulletin|volume=66|issue=3|pages=179–188|doi=10.1016/j.brainresbull.2005.05.009|issn=0361-9230|pmid=16023915}}</ref><ref>{{Cite journal|last=Riley|first=Joseph|last2=Robinson|first2=Michael|last3=Wise|first3=Emily|last4=Myers|first4=Cynthia|last5=Fillingim|first5=Roger|date=Jan 1998|title=Sex differences in the perception of noxious experimental stimuli: a meta-analysis|url=http://insights.ovid.com/|journal=Pain|language=ENGLISH|volume=74|issue=2-3|pages=181–187|doi=10.1016/S0304-3959(97)00199-1|issn=0304-3959|pmid=9520232}}</ref> Progesterone has been shown in mice to prevent neurodegeneration, increase muscle strength, and enhance respiratory activity. The same study showed that progesterone blocks pro-inflammatory mediators, lessened Iba1+ microglial cells, and decreased symptoms of brain inflammation in mice. It also reduced the production of [[nitric oxide]] and [[TNF-α]].<ref>{{Cite journal|last=Nicola|first=A. F. De|last2=Deniselle|first2=M. C. Gonzalez|last3=Garay|first3=L.|last4=Meyer|first4=M.|last5=Gargiulo‐Monachelli|first5=G.|last6=Guennoun|first6=R.|last7=Schumacher|first7=M.|last8=Carreras|first8=M. C.|last9=Poderoso|first9=J. J.|date=2013|title=Progesterone Protective Effects in Neurodegeneration and Neuroinflammation|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/jne.12043|journal=Journal of Neuroendocrinology|language=en|volume=25|issue=11|pages=1095–1103|doi=10.1111/jne.12043|issn=1365-2826}}</ref> Progesterone is neuroprotective, anti-inflammatory, and promyelinating, and could present great benefits for neurological illnesses.

In conclusion to a 2018 survey of literature related to neurosteroids, Del Río et. al. wrote the following:<blockquote>"The present review shows that fluctuations in steroid hormones, influenced by factors such as age and health status, have consequences at the level of CNS [central nervous system] and PNS [peripheral nervous system]. Utilizing both classical and non-classical pathways, neurosteroids participate in the physiological regulation of neurogenesis, neuronal survival, synaptic function, and myelin formation, thus influencing neuronal plasticity. Because of these effects, neurosteroids will have different modulatory actions, exerting control over mood, cognition, and behavior. Additionally, they have a neuroprotective role in relation to certain neurocognitive pathologies."<ref>{{Cite journal|last=Del Río|first=Juan Pablo|last2=Alliende|first2=María I.|last3=Molina|first3=Natalia|last4=Serrano|first4=Felipe G.|last5=Molina|first5=Santiago|last6=Vigil|first6=Pilar|date=2018-05-23|title=Steroid Hormones and Their Action in Women's Brains: The Importance of Hormonal Balance|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974145/|journal=Frontiers in Public Health|volume=6|doi=10.3389/fpubh.2018.00141|issn=2296-2565|pmc=5974145|pmid=29876339}}</ref></blockquote>

=== Pain Modulation ===
Neurosteroids have been found to affect the sensory nervous system in ways that may prevent central sensitization, the process by which the NS becomes heightened to pain perception, and therefore reduce chronic pain. Researchers believe that both the administration of synthetic neurosteroids and treatments that promote the genesis of endogenous neurosteroids like progesterone could hold great promise for future pain management therapies. The latter has proven successful in several animal studies measuring neuropathic, inflammatory, and post-surgical pain models.<ref>{{Cite journal|last=Todorovic|first=Slobodan M.|last2=Jevtovic-Todorovic|first2=Vesna|last3=Covey|first3=Douglas F.|last4=Joksimovic|first4=Sonja L.|date=2018|title=Neurosteroids in Pain Management: A New Perspective on an Old Player|url=https://www.frontiersin.org/articles/10.3389/fphar.2018.01127/full|journal=Frontiers in Pharmacology|language=English|volume=9|doi=10.3389/fphar.2018.01127|issn=1663-9812}}</ref><ref>{{Cite journal|last=Kastrup|first=Y|last2=Hallbeck|first2=M|last3=Amandusson|first3=Å|last4=Hirata|first4=S|last5=Hermanson|first5=O|last6=Blomqvist|first6=A|date=1999-11-12|title=Progesterone receptor expression in the brainstem of the female rat|url=http://www.sciencedirect.com/science/article/pii/S0304394099007533|journal=Neuroscience Letters|volume=275|issue=2|pages=85–88|doi=10.1016/S0304-3940(99)00753-3|issn=0304-3940}}</ref>

=== Autonomic Nervous System ===
Progesterone has been shown to bind to receptors in the brainstem of rats that modulate pain as well as those that regulate the autonomic nervous system (ANS), the part of the NS that controls unconscious processes like heart rate, breathing, and digestion.<ref>{{Cite journal|last=Kastrup|first=Y|last2=Hallbeck|first2=M|last3=Amandusson|first3=Å|last4=Hirata|first4=S|last5=Hermanson|first5=O|last6=Blomqvist|first6=A|date=1999-11-12|title=Progesterone receptor expression in the brainstem of the female rat|url=http://www.sciencedirect.com/science/article/pii/S0304394099007533|journal=Neuroscience Letters|volume=275|issue=2|pages=85–88|doi=10.1016/S0304-3940(99)00753-3|issn=0304-3940}}</ref> Research has also shown increased autonomic cardiac function in human females during the ovulation phase of their cycles, when progesterone begins to rise rapidly.<ref>{{Cite journal|last=Little|first=Betsy Carter|last2=Zahn|first2=Theodore P.|date=1974|title=Changes in Mood and Autonomic Functioning During the Menstrual Cycle|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1469-8986.1974.tb01118.x|journal=Psychophysiology|language=en|volume=11|issue=5|pages=579–590|doi=10.1111/j.1469-8986.1974.tb01118.x|issn=1469-8986}}</ref> However, it is unknown whether this is a result of progesterone alone or progesterone combined with estrogen. The latter theory is supported by studies that have shown autonomic regulation of cardiac function suffers during the Luteal Phase and that estrogen is likely to play a stronger role in sympathetic cardiac balance than progesterone.<ref>{{Cite journal|last=Fuenmayor|first=Abdel J.|last2=Ramı́rez|first2=Leonardo|last3=Fuenmayor|first3=Abdel M.|date=2000-02-15|title=Left ventricular function and autonomic nervous system balance during two different stages of the menstrual cycle|url=http://www.sciencedirect.com/science/article/pii/S016752739900193X|journal=International Journal of Cardiology|volume=72|issue=3|pages=243–246|doi=10.1016/S0167-5273(99)00193-X|issn=0167-5273}}</ref><ref>{{Cite journal|last=Mercuro|first=Giuseppe|last2=Zoncu|first2=Sandra|last3=Saiu|first3=Francesca|last4=Mascia|first4=Monica|last5=Melis|first5=Gian Benedetto|last6=Rosano|first6=Giuseppe M. C.|date=2004-02-20|title=Menopause induced by oophorectomy reveals a role of ovarian estrogen on the maintenance of pressure homeostasis|url=https://www.ncbi.nlm.nih.gov/pubmed/14757272|journal=Maturitas|volume=47|issue=2|pages=131–138|issn=0378-5122|pmid=14757272}}</ref>

=== Mood ===
Progesterone is well-known to have a calming effect and promote feelings of "elation and vigor."<ref>{{Cite journal|last=Little|first=Betsy Carter|last2=Zahn|first2=Theodore P.|date=1974|title=Changes in Mood and Autonomic Functioning During the Menstrual Cycle|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1469-8986.1974.tb01118.x|journal=Psychophysiology|language=en|volume=11|issue=5|pages=579–590|doi=10.1111/j.1469-8986.1974.tb01118.x|issn=1469-8986}}</ref> Some medical experts believe low progesterone to estrogen ratios are often the source of anxiety disorders.

== Progesterone and Collagen ==

== See also ==

*[[Menstrual cycle]]
*[[Pregnancy]]

==References==
<references />
[[Category:Neurotransmitters and hormones]]
[[Category:Sex hormones]]
[[Category:Hormones]]

Progesterone

2019-08-09T01:56:38Z

Mbunke:added more to inflammation

Progesterone is a steroid and sex hormone that is created endogenously (by our own bodies). It is the primary hormone in the steroid class ''progestogens''. Although widely known to play a large role in the menstrual cycle and pregnancy, scientists are just beginning to understand the enormous range of effects progesterone can have on the human body and its many systems. The word progesterone comes from the Latin ''pro-'', meaning "for," and ''gest-'', referring to pregnancy (as in "gestation"). It is commonly called the "pregnancy hormone."

=== Progesterone vs. Progestins ===
''Progestins'' are a synthetic form of progesterone that differ in molecular makeup from the progesterone created by our bodies. Progestins are used by pharmaceutical companies in medications and contraceptives. They are purposefully created to differ in structure from progesterone for patenting purposes (it is often not possible to patent a chemical as it exists in nature) and in order to create desired side-effects such as those that prevent pregnancy from occurring. There are around 10 different progestins used in contraceptive pills.

Women that take progestins should be aware that these hormones do not perfectly mimic natural progesterone, because they can cause unwanted side-effects, ranging in severity from acne to breast cancer.<ref>{{Cite journal|last=Gebel Berg|first=Erika|date=2015-03-25|title=The Chemistry of the Pill|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827491/|journal=ACS Central Science|volume=1|issue=1|pages=5–7|doi=10.1021/acscentsci.5b00066|issn=2374-7943|pmc=4827491|pmid=27162937}}</ref><ref>{{Cite journal|last=Santen|first=Richard J|date=2003-11-01|title=Risk of breast cancer with progestins: critical assessment of current data|url=http://www.sciencedirect.com/science/article/pii/S0039128X03001387|journal=Steroids|series=The 2nd International Symposium on Progestins, Progesterone Receptor Modulators and Progesterone Antagonists|volume=68|issue=10|pages=953–964|doi=10.1016/S0039-128X(03)00138-7|issn=0039-128X}}</ref>

==Bio-Identical Progesterone & BHRT ==
Many functional medicine doctors have begun supplementing imbalanced hormone levels with bio-identical hormone replacement therapy (BHRT). The term bio-identical distinguishes these hormone supplements from the often used synthetic derivatives created by pharmaceutical companies. The use of the latter is widely known and highly conventional among mainstream medicine, whereas BHRT is most often only heard of in functional or integrative medicine. Bio-identical hormone supplements are identical in molecular structure to the natural hormones your body creates. A practitioner who uses BHRT will likely measure your hormone levels via saliva or blood sample, and prescribe your hormones through a compounding pharmacy. Bio-identical progesterone is synthesized from the naturally occurring diosgenin in wild yams or from the stigmasterol found in soy beans and can be taken as a transdermal cream, pill, or vaginal gel.<ref>{{Cite web|url=https://www.health.harvard.edu/womens-health/what-are-bioidentical-hormones|title=What are bioidentical hormones?|last=Publishing|first=Harvard Health|website=Harvard Health|access-date=2019-08-08}}</ref><ref>{{Cite web|url=http://pennstatehershey.adam.com/content.aspx?productId=107&pid=33&gid=000280|title=Complementary and Alternative Medicine - Penn State Hershey Medical Center - Wild yam - Penn State Hershey Medical Center|website=pennstatehershey.adam.com|access-date=2019-08-08}}</ref><ref>{{Cite web|url=https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/stigmasterol|title=Stigmasterol - an overview {{!}} ScienceDirect Topics|website=www.sciencedirect.com|access-date=2019-08-08}}</ref>

Although bio-identical progesterone is sometimes considered more "natural" than progestins because its molecular structure is identical to the progesterone created by our bodies, both progestins and bio-identical progesterone are synthesized by humans. Many believe bio-identical progesterone to be safe, but more research is needed to confirm the long-term side effects.

== Role in the Menstrual Cycle ==

=== Cycle Overview ===
At the beginning of a woman's cycle, the hypothalamus begins to secrete Gonadotropin Releasing Hormone (GnRH), stimulating the pituitary to create Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH), which travel to the ovaries. FSH causes the ovaries to stimulate the maturation process of follicles. Several follicles, each of which stores an egg, begin to grow as they mature, and in the process releasing estrogen. This estrogen produces a negative feedback during the first 10 days of the cycle that tells to the pituitary to inhibit the release of LH. It is important to note that ''low'' levels of estrogen will inhibit the release of LH from the pituitary, while ''high'' levels will stimulate it.

As estrogen continues to rise due to the maturing follicles, is also causes FSH levels to fall steadily (low estrogen triggers the release of FSH). Around day 10 of the cycle, estrogen levels reach a threshold which stops the negative feedback loop and begins a positive one resulting in the secretion of LH by the pituitary. The resulting spike in LH triggers the most mature follicle to release an egg (or oocyte); this is known as ovulation.

After ovulation, the empty follicle will begin to die. This dying follicle is called a corpus luteum. As the corpus luteum degrades, it secretes estrogen, inhibin, and progesterone. Inhibin provides a negative feedback to the pituitary to suppress the production of FSH. Progesterone provides a similar feedback to prohibit the release of GnRH, which in turn decreases the levels of LH and FSH. It also stimulates endometrial growth (the lining of the uterus).

As the corpus luteum degenerates, it will secrete fewer and fewer hormones, and progesterone, estrogen, and inhibin will steadily decrease. This decrease in progesterone allows for the secretion of GnRH to begin again, and the cycle repeats again, unless the egg becomes fertilized. If the egg is not fertilized, the decreasing levels of progesterone can no longer maintain the lining of the uterine wall, so the wall dies and sheds out of the body, resulting in menstruation.

Progesterone only exists in high levels during the second half of the menstrual cycle, the Luteal Phase.<ref>{{Cite journal|last=Reed|first=Beverly G.|last2=Carr|first2=Bruce R.|date=2000|editor-last=Feingold|editor-first=Kenneth R.|editor2-last=Anawalt|editor2-first=Bradley|editor3-last=Boyce|editor3-first=Alison|editor4-last=Chrousos|editor4-first=George|editor5-last=Dungan|editor5-first=Kathleen|editor6-last=Grossman|editor6-first=Ashley|editor7-last=Hershman|editor7-first=Jerome M.|editor8-last=Kaltsas|editor8-first=Gregory|editor9-last=Koch|editor9-first=Christian|title=The Normal Menstrual Cycle and the Control of Ovulation|url=http://www.ncbi.nlm.nih.gov/books/NBK279054/|location=South Dartmouth (MA)|publisher=MDText.com, Inc.|pmid=25905282}}</ref> In the absence of fertilization, the corpus luteum will last for 11 to 17 days; it is during these days a woman can expect her progesterone levels to be highest.

===Exogenous Progesterone, Preventing Ovulation, and Contraceptives ===
Many contraceptives use progestins (synthetic progesterone) to prevent ovulation. They can also prevent pregnancy by thickening the cervical mucus, which blocks sperm from entering the uterus, and thinning the lining of the uterine wall, which prevents implantation of a fertilized egg (although endogenous progesterone helps to ''thicken'' this lining, the slightly different structure of some progestins results in the opposite effect). The most common form of birth control, combined oral contraceptive pills, also simply called "The Pill," uses progestins and estrogen to prevent pregnancy.

==== How Progestins & Progesterone Prevent Ovulation ====
The chemical process by which progesterone and progestins prevent ovulation centers around their ability to stop the release of Luteinizing Hormone (LH) by the anterior pituitary. Progesterone/progestins naturally create a negative feedback to the Hypothalamus, causing the latter to inhibit the release of Gonadotropin Releasing Hormone (GnRH). Without enough GnRH to stimulate the release of LH from the pituitary, LH levels will not spike as they usually around day 13-14 in the cycle, and ovulation will not occur.

==== Endogenous Progesterone Levels in Luteal Phase when Ovulation Fails ====
This failure to ovulates means no follicle will release an egg and degrade into a corpus luteum. The corpus luteum (CL), or dying follicle, is the main source of endogenous progesterone in the female cycle, therefore without the CL, endogenous progesterone levels will remain low during the second half of the cycle. Women taking either progestins or exogenous bio-identical progesterone at certain levels should be aware of this process halting the production of endogenous progesterone may be taking place, especially for those trying to conceive and because this hormone plays an important role not only in reproduction, but in the brain as well (see "[[Progesterone in the Brain]]" below).

There is currently no research suggesting universally "safe" levels of exogenous bio-identical progesterone doses that will not prevent ovulation from occurring. The hormone feedback loops that are integral to the female cycle are incredibly complex and sensitive, and exogenous progesterone is metabolized at different rates in different females. These factors make ovulation-safe levels very difficult to predict.

== Reference Ranges ==
Reference ranges vary slightly by lab; the following is an example of reference ranges for progesterone levels in blood serum used by the Mayo Clinic:<ref>{{Cite web|url=https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/8141|title=PGSN - Clinical: Progesterone, Serum|website=www.mayocliniclabs.com|access-date=2019-08-08}}</ref>
{| class="wikitable"
! colspan="5" |Progesterone Reference Ranges (ng/mL)*
|-
| rowspan="5" |Males
|< 4 weeks
| colspan="3" |not established
|-
|4 weeks - < 12 mos.
| colspan="3" |< or = 0.66
|-
|12 mos. - 9 yrs.
| colspan="3" |< or = 0.35
|-
|10 - 17 yrs.
| colspan="3" |< or = 0.5
|-
|> or = 18 yrs.
| colspan="3" |< 0.20
|-
| rowspan="10" |Females
| rowspan="3" |Pre-pubescent
|< 4 days
| colspan="2" |not established
|-
|4 days - < 12 mos.
| colspan="2" |< or = 1.3
|-
|12 mos. - 9 yrs.
| colspan="2" |< or = 0.35
|-
| rowspan="7" |Adult
| rowspan="3" |> or = 18 yrs.
|Follicular phase
|< or = 0.89
|-
|Ovulation
|< or = 12
|-
|Luteal phase
|1.8 - 24
|-
| rowspan="3" |Pregnancy
|1st trimester
|11-44
|-
|2nd trimester
|25-83
|-
|3rd trimester
|58-214
|-
|Post-menopausal
| colspan="2" |< or = 0.20
|}
''*Reference intervals are based on central 90th% of healthy population''

==Progesterone & Estrogen: A Balancing Act ==
One of the reasons it is difficult to measure the effects of progesterone and estrogen is that these two primary female sex hormones work in concert with each other, and it is their therefore often the case that their ''ratio'' is more important than their independent levels in the body. Many of the functions of estrogens are countered by progesterone including tissue and bone growth, inflammation, immune function, and uterine muscle contraction. When progesterone does not exist in sufficient levels in the body, it results in "estrogen dominance," which can lead to breast cancer, endometriosis, and other pathologies It is in establishing the correct levels of ''both'' estrogens and progesterone that a healthy homeostasis is achieved and the pathogenesis of endometriosis, infertility, cancer, and more can be diminished.

{| class="wikitable"
|+Estrogen's Functions & Progesterone's Counter-functions
|'''Estrogen'''
|'''Progesterone'''
|-
|Stimulates tissue growth
|Stops tissue growth, promotes cell death
|-
|Decreases the rate of bone breakdown
|Stimulates bone osteoblasts
|-
|Stimulates contraction of uterine muscles
|Decreases uterine muscle contractions, promotes uterine muscle relaxation
|-
|Promotes edema (fluid-retention)
|Decreases edema
|-
|Most often promotes inflammation
|Most often anti-inflammatory, suppresses pro-inflammatory cytokines
|-
|Promotes immune activation (influx of neutrophils and activation of macrophages)
|Immunosuppressant, promotes immunotolerance
|}

=== Inflammation ===
Although estrogen has some anti-inflammatory effects, it most often functions as a pro-inflammatory hormone. Progesterone, on the other hand, which often down-regulates estrogen-mediated actions, functions as a powerful anti-inflammatory steroid. Both are critical in maintaining a normal menstrual cycle and healthy pregnancies. Estrogen's inflammatory effects in the absence of progesterone's anti-inflammatory action are necessary for stimulating the shedding of the uterine wall in menstruation, and some scientists even describe menstruation itself as an "acute inflammatory response of ESCs [endometrial stromal cells] to progesterone withdrawal."<ref>{{Cite web|url=https://profile.thieme.de/HTML/sso/ejournals/login.htm?rdeLocaleAttr=en&type=default&subsidiary=www.thieme-connect.com&hook_url=https%3A%2F%2Fwww.thieme-connect.com%2Fproducts%2Fejournals%2Fhtml%2F10.1055%2Fs-0034-1376355|title=Thieme - Login|website=profile.thieme.de|doi=10.1055/s-0034-1376355#jr00900-120|access-date=2019-08-09}}</ref>

Progesterone's anti-inflammatory effect has also been found to aid in recovery from traumatic brain injury in rats, fight gingivitis in monkeys, and decrease signs of autoimmune encephalomyelitis (EAE) in mice.<ref>{{Cite journal|last=He|first=Jun|last2=Evans|first2=Chheng-Orn|last3=Hoffman|first3=Stuart W.|last4=Oyesiku|first4=Nelson M.|last5=Stein|first5=Donald G.|date=2004-10-01|title=Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury|url=http://www.sciencedirect.com/science/article/pii/S0014488604002390|journal=Experimental Neurology|volume=189|issue=2|pages=404–412|doi=10.1016/j.expneurol.2004.06.008|issn=0014-4886}}</ref><ref>{{Cite journal|last=Deasy|first=M. J.|last2=Grota|first2=L. J.|last3=Kennedy|first3=J. E.|date=1972|title=The effect of estrogen progesterone and cortisol on gingival inflammation|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0765.1972.tb00636.x|journal=Journal of Periodontal Research|language=en|volume=7|issue=2|pages=111–124|doi=10.1111/j.1600-0765.1972.tb00636.x|issn=1600-0765}}</ref><ref>{{Cite journal|last=Nicola|first=A. F. De|last2=Deniselle|first2=M. C. Gonzalez|last3=Garay|first3=L.|last4=Meyer|first4=M.|last5=Gargiulo‐Monachelli|first5=G.|last6=Guennoun|first6=R.|last7=Schumacher|first7=M.|last8=Carreras|first8=M. C.|last9=Poderoso|first9=J. J.|date=2013|title=Progesterone Protective Effects in Neurodegeneration and Neuroinflammation|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/jne.12043|journal=Journal of Neuroendocrinology|language=en|volume=25|issue=11|pages=1095–1103|doi=10.1111/jne.12043|issn=1365-2826}}</ref> It is known to suppress pro-inflammatory cytokines,<ref>{{Cite journal|last=Munoz-Suano|first=Alba|last2=Hamilton|first2=Alexander B.|last3=Betz|first3=Alexander G.|date=2011-04-13|title=Gimme shelter: the immune system during pregnancy|url=http://dx.doi.org/10.1111/j.1600-065x.2011.01002.x|journal=Immunological Reviews|volume=241|issue=1|pages=20–38|doi=10.1111/j.1600-065x.2011.01002.x|issn=0105-2896}}</ref> such as the inhibition [[IL-6]] and [[IL-8]] in the inflammatory response to [[lipopolysaccharides]] in human uterine cervical fibroblasts.<ref>http://www.sciencedirect.com/science/article/pii/S0024320512000136</ref>

It is unknown whether progesterone functions independently as an anti-inflammatory, or whether it must work in concert in estrogen to have this effect.

==== Progesterone Resistance & Inflammation in Endometriosis ====
Endometriosis is a condition in which tissue grows not only on the internal walls of the uterus, on the ovaries, fallopian tubes, and external uterine walls as well. It leads to pain and sometimes infertility. Research suggests that the etiology of endometriosis centers heavily on a disruption of estrogen-progesterone homeostasis in the uterus, caused by "progesterone resistance," which therefore leads to increased inflammation.<ref>{{Cite web|url=https://profile.thieme.de/HTML/sso/ejournals/login.htm?rdeLocaleAttr=en&type=default&subsidiary=www.thieme-connect.com&hook_url=https%3A%2F%2Fwww.thieme-connect.com%2Fproducts%2Fejournals%2Fhtml%2F10.1055%2Fs-0034-1376355|title=Thieme - Login|website=profile.thieme.de|doi=10.1055/s-0034-1376355#jr00900-120|access-date=2019-08-09}}</ref> This progesterone resistance may lead to increased production of estrogen and increased pro-inflammatory cytokine presence including IL-1β, TNF-α, LIF, IL-6, IL-8, IL-11, NF-kB, p53, and STAT3. While these cytokines aid in embryonic implantation, levels that are too high or last too long can lead to aberrant outcomes like endometriosis. Through studying the effects of progesterone on endometriosis and other conditions related to estrogen-dominance, many researchers are optimistic about the development of future treatment.<ref>{{Cite web|url=https://profile.thieme.de/HTML/sso/ejournals/login.htm?rdeLocaleAttr=en&type=default&subsidiary=www.thieme-connect.com&hook_url=https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0034-1376355|title=Thieme - Login|website=profile.thieme.de|doi=10.1055/s-0034-1376355|access-date=2019-08-09}}</ref>

==== Pro-inflammatory vs. Anti-inflammatory Effects ====
Deciphering the roles of progesterone and estrogen is extremely difficult because both can have a wide range of effects. Both hormones can have pro- ''and'' anti-inflammatory functions, depending on the physiological circumstances. Progesterone and estrogen act on cells by binding to specific receptors. Progesterone binds to two main receptors: PR-A and PR-B. When binding to the latter receptor, progesterone decreases inflammation and increases responsiveness to estrogen, while binding to the former has the converse effect.

== Progesterone in the Brain ==

=== Progesterone as a Neurosteroid ===
Progesterone not only plays a major role in female reproduction, but has many other important roles in both males and females. One such role is as a powerful neurosteroid. Neurosteroids are steroids synthesized in the brain that regulate the excitability of neurons. It has been shown to be important in myelin repair in rodents in the sciatic nerve. In one study, the administration of progesterone to the site of brain lesions led to the regeneration of new myelin sheaths.<ref>{{Cite journal|last=Baulieu|first=E.|last2=Schumacher|first2=M.
|date=Oct 2000|title=Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination|url=https://www.ncbi.nlm.nih.gov/pubmed/11108866|journal=Steroids|volume=65|issue=10-11|pages=605–612|issn=0039-128X|pmid=11108866}}</ref> Neurosteroids can have powerful effects on both pain perception and inflammation, and research has suggested that female sex hormones like progesterone play a key role in modulating chronic pain.<ref>{{Cite journal|last=Kuba|first=Tzipora|last2=Quinones-Jenab|first2=Vanya|date=2005-08-15|title=The role of female gonadal hormones in behavioral sex differences in persistent and chronic pain: clinical versus preclinical studies|url=https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16023915|journal=Brain Research Bulletin|volume=66|issue=3|pages=179–188|doi=10.1016/j.brainresbull.2005.05.009|issn=0361-9230|pmid=16023915}}</ref><ref>{{Cite journal|last=Riley|first=Joseph|last2=Robinson|first2=Michael|last3=Wise|first3=Emily|last4=Myers|first4=Cynthia|last5=Fillingim|first5=Roger|date=Jan 1998|title=Sex differences in the perception of noxious experimental stimuli: a meta-analysis|url=http://insights.ovid.com/|journal=Pain|language=ENGLISH|volume=74|issue=2-3|pages=181–187|doi=10.1016/S0304-3959(97)00199-1|issn=0304-3959|pmid=9520232}}</ref> Progesterone has been shown in mice to prevent neurodegeneration, increase muscle strength, and enhance respiratory activity. The same study showed that progesterone blocks pro-inflammatory mediators, lessened Iba1+ microglial cells, and decreased symptoms of brain inflammation in mice. It also reduced the production of [[nitric oxide]] and [[TNF-α]].<ref>{{Cite journal|last=Nicola|first=A. F. De|last2=Deniselle|first2=M. C. Gonzalez|last3=Garay|first3=L.|last4=Meyer|first4=M.|last5=Gargiulo‐Monachelli|first5=G.|last6=Guennoun|first6=R.|last7=Schumacher|first7=M.|last8=Carreras|first8=M. C.|last9=Poderoso|first9=J. J.|date=2013|title=Progesterone Protective Effects in Neurodegeneration and Neuroinflammation|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/jne.12043|journal=Journal of Neuroendocrinology|language=en|volume=25|issue=11|pages=1095–1103|doi=10.1111/jne.12043|issn=1365-2826}}</ref> Progesterone is neuroprotective, anti-inflammatory, and promyelinating, and could present great benefits for neurological illnesses.

== See also ==

*[[Menstrual cycle]]
*[[Pregnancy]]

==References==
<references />
[[Category:Neurotransmitters and hormones]]
[[Category:Sex hormones]]
[[Category:Hormones]]

Progesterone

2019-08-08T22:14:55Z

Mbunke:added ref ranges

Progesterone

2019-08-08T21:44:13Z

Mbunke:Added lots more content

Progesterone

2019-08-08T21:08:15Z

Mbunke:/* Role in the Menstrual Cycle */

Menstrual cycle

2019-08-08T06:01:15Z

Mbunke:/* Cycles and phases */

The [[menstrual cycle]] plays a role in the variation of symptoms and symptom severity in many [[immunological]], [[neurological]], and [[female predominant diseases]].

== Cycles and phases ==

=== Follicular Phase ===
At the beginning of a woman's cycle, the hypothalamus begins to secrete Gonadotropin Releasing Hormone (GnRH), stimulating the pituitary to create Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH), which travel to the ovaries. FSH causes the ovaries to stimulate the maturation process of follicles. Several follicles, each of which stores an egg, begin to grow as they mature, and in the process releasing estrogen. This estrogen produces a negative feedback during the first 10 days of the cycle that tells to the pituitary to inhibit the release of LH. It is important to note that ''low'' levels of estrogen will inhibit the release of LH from the pituitary, while ''high'' levels will stimulate it.

=== Ovulation ===
As estrogen continues to rise due to the maturing follicles, is also causes FSH levels to fall steadily (low estrogen triggers the release of FSH). Around day 10 of the cycle, estrogen levels reach a threshold which stops the negative feedback loop and begins a positive one resulting in the secretion of LH by the pituitary. The resulting spike in LH triggers the most mature follicle to release an egg (or oocyte); this is known as ovulation.

=== Luteal Phase ===
After ovulation, the empty follicle will begin to die. This dying follicle is called a corpus luteum. As the corpus luteum degrades, it secretes estrogen, inhibin, and progesterone. Inhibin provides a negative feedback to the pituitary to suppress the production of FSH. Progesterone provides a similar feedback to prohibit the release of GnRH, which in turn decreases the levels of LH and FSH. It also stimulates endometrial growth (the lining of the uterus).

As the corpus luteum degenerates, it will secrete fewer and fewer hormones, and progesterone, estrogen, and inhibin will steadily decrease. This decrease in progesterone allows for the secretion of GnRH to begin again, and the cycle repeats again, unless the egg becomes fertilized. If the egg is not fertilized, the decreasing levels of progesterone can no longer maintain the lining of the uterine wall, so the wall dies and sheds out of the body, resulting in menstruation.<ref>{{Cite journal|last=Reed|first=Beverly G.|last2=Carr|first2=Bruce R.|date=2000|editor-last=Feingold|editor-first=Kenneth R.|editor2-last=Anawalt|editor2-first=Bradley|editor3-last=Boyce|editor3-first=Alison|editor4-last=Chrousos|editor4-first=George|editor5-last=Dungan|editor5-first=Kathleen|editor6-last=Grossman|editor6-first=Ashley|editor7-last=Hershman|editor7-first=Jerome M.|editor8-last=Kaltsas|editor8-first=Gregory|editor9-last=Koch|editor9-first=Christian|title=The Normal Menstrual Cycle and the Control of Ovulation|url=http://www.ncbi.nlm.nih.gov/books/NBK279054/|location=South Dartmouth (MA)|publisher=MDText.com, Inc.|pmid=25905282}}</ref>

== Immune changes ==

Populations of [[Treg]]s increase peak just before ovulation and bottom out during the [[luteal phase]], just before [[menstruation]].{{Citation needed}}

[[Progesterone]] and [[estrogen]] have [[anti-inflammatory]] effects.{{Citation needed}}

==Health effects in ME/CFS ==

Women with [[chronic fatigue syndrome]] report higher rates of [[polycystic ovarian syndrome]] (PCOS) and anovulatory cycles, higher rates of [[dysmenorrhea]] and higher rates of [[endometriosis]].<ref name=":0">{{Cite journal|last=Allen|first=Peggy Rosati|date=Jul 2008|title=Chronic fatigue syndrome: implications for women and their health care providers during the childbearing years|url=https://www.ncbi.nlm.nih.gov/pubmed/18586181|journal=Journal of Midwifery & Women's Health|volume=53|issue=4|pages=289–301; quiz 399|doi=10.1016/j.jmwh.2007.12.001|issn=1542-2011|pmid=18586181}}</ref>

Women who develop CFS report at higher rates a history of irregular cycles, [[amenorrhea]], [[anovolutory]] cycles and sporadic bleeding between periods.<ref>{{Cite journal|last=Komaroff|first=AnthonyL|last2=Dailey|first2=Christine|last3=Hall|first3=JanetE|last4=Signorello|first4=LisaB|last5=Harlow|first5=BernardL|date=1998-09-28|title=Reproductive correlates of chronic fatigue syndrome|url=https://www.amjmed.com/article/S0002-9343(98)00173-9/abstract|journal=The American Journal of Medicine|language=English|volume=105|issue=3|pages=94S–99S|doi=10.1016/S0002-9343(98)00173-9|issn=0002-9343}}</ref>

Numerous outbreaks of [[epidemic myalgic encephalomyelitis]] noted menstrual irregularities and a tendency toward relapse before or during menstruation.<ref name="Shelokov, 1957">{{Citation
| last1 = Shelokov | first1 = Alexis | authorlink1 =
| last2 = Habel | first2 = Karl | authorlink2 =
| last3 = Verder | first3 = Elizabeth | authorlink3 =
| last4 = Welsh | first4 = William | authorlink4 =
| title = Epidemic Neuromyasthenia — An Outbreak of Poliomyelitis-like Illness in Student Nurses
| journal = New England Journal of Medicine | volume = 1957 | issue = 257 | page = 345-355
| date = August 1957
| doi = 10.1056/NEJM195708222570801
}}</ref><ref name=":1">{{Cite journal|last=Albrecht|first=Robert|date=March 21, 1964|title=Epidemic Neuromyasthenia Outbreak in a Convent in New York State|url=https://www.ncbi.nlm.nih.gov/pubmed/14100144|journal=Journal of the American Medical Association|volume=187|pages=904-907|via=}}</ref><ref name="Poskanzer, 19572">{{Citation
| last1 = Poskanzer | first1 = David C. | authorlink1 =
| last2 = Henderson | first2 = Donald A. | authorlink2 =
| last3 = Kunkle | first3 = E. Charles | authorlink3 =
| last4 = Kalter | first4 = Seymour S. | authorlink4 =
| last5 = Clement | first5 = Walter B. | authorlink5 =
| last6 = Bond | first6 = James O. | authorlink6 =
| title = Epidemic Neuromyasthenia — An Outbreak in Punta Gorda, Florida
| journal = New England Journal of Medicine | volume = 1957 | issue = 257 | page = 356-364
| date = 1957
| pmid = 13464939
| doi = 10.1056/NEJM195708222570802
| url = http://www.nejm.org/doi/full/10.1056/NEJM195708222570802
}}</ref>

== Health effects in other conditions ==

The menstrual cycle can have effects on the timing and severity of symptoms of women suffering from many different conditions, including [[epilepsy]], [[migraine]]s, [[asthma]], [[rheumatoid arthritis]] and [[irritable bowel syndrome]].<ref name=":2">{{Cite journal|last=Reid|first=Robert L.|last2=Case|first2=Allison M.|date=1998-07-13|title=Effects of the Menstrual Cycle on Medical Disorders|url=https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/208109|journal=Archives of Internal Medicine|language=en|volume=158|issue=13|pages=1405–1412|doi=10.1001/archinte.158.13.1405|issn=0003-9926}}</ref>

Many women with [[epilepsy]] have patterns of seizure activity linked to their menstrual cycles, called [[catamenial epilepsy]].<ref>{{Cite journal|last=Herzog|first=Andrew G.|date=2008-03-01|title=Catamenial epilepsy: Definition, prevalence pathophysiology and treatment|url=https://www.seizure-journal.com/article/S1059-1311(07)00233-6/abstract|journal=Seizure - European Journal of Epilepsy|language=English|volume=17|issue=2|pages=151–159|doi=10.1016/j.seizure.2007.11.014|issn=1059-1311|pmid=18164632}}</ref><ref>{{Cite journal|last=Herzog|first=Andrew G.|last2=Harden|first2=Cynthia L.|last3=Liporace|first3=Joyce|last4=Pennell|first4=Page|last5=Schomer|first5=Donald L.|last6=Sperling|first6=Michael|last7=Fowler|first7=Kristen|last8=Nikolov|first8=Blagovast|last9=Shuman|first9=Sevie|date=2004|title=Frequency of catamenial seizure exacerbation in women with localization-related epilepsy|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.20214|journal=Annals of Neurology|language=en|volume=56|issue=3|pages=431–434|doi=10.1002/ana.20214|issn=1531-8249}}</ref><ref>{{Cite journal|last=Herzog|first=Andrew G.|last2=Klein|first2=Pavel|last3=Rand|first3=Bernard J.|date=1997|title=Three Patterns of Catamenial Epilepsy|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1528-1157.1997.tb01197.x|journal=Epilepsia|language=en|volume=38|issue=10|pages=1082–1088|doi=10.1111/j.1528-1157.1997.tb01197.x|issn=1528-1167}}</ref><ref>http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2006.00672.x/abstract</ref> Seizure activity increases just before ovulation and just before menstruation.<ref>{{Cite journal|last=Reid|first=Robert L.|last2=Case|first2=Allison M.|date=1998-07-13|title=Effects of the Menstrual Cycle on Medical Disorders|url=https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/208109|journal=Archives of Internal Medicine|language=en|volume=158|issue=13|pages=1405–1412|doi=10.1001/archinte.158.13.1405|issn=0003-9926}}</ref>

Abrupt estrogen withdrawal, such as what occurs just prior to menstruation, can trigger [[migraine]]s.<ref>{{Cite journal|last=Brandes|first=Jan Lewis|date=2006-04-19|title=The Influence of Estrogen on Migraine: A Systematic Review|url=https://jamanetwork.com/journals/jama/fullarticle/202685|journal=JAMA|language=en|volume=295|issue=15|pages=1824–1830|doi=10.1001/jama.295.15.1824|issn=0098-7484}}</ref><ref name=":2" /> Women with [[rheumatoid arthritis]] experienced reduced symptoms after ovulation, owing potentially to the anti-inflammatory effects of [[progesterone]] and [[estrogen]].<ref>{{Cite journal|last=Latman|first=Neal S.|date=1983-06-01|title=Relation of menstrual cycle phase to symptoms of rheumatoid arthritis|url=https://www.amjmed.com/article/0002-9343(83)90789-1/abstract|journal=The American Journal of Medicine|language=English|volume=74|issue=6|pages=957–960|doi=10.1016/0002-9343(83)90789-1|issn=0002-9343}}</ref>

In a retrospective study, 72% of women with [[fibromyalgia]] reported a worsening of symptoms just before their periods.<ref>{{Cite journal|last=Østensen|first=Monika|last2=Rugelsjoen|first2=Anne|last3=Wigers|first3=Sigrid Horven|date=1997-01-01|title=The Effect of Reproductive Events and Alterations of Sex Hormone Levels on the Symptoms of Fibromyalgia|url=https://doi.org/10.3109/03009749709065698|journal=Scandinavian Journal of Rheumatology|volume=26|issue=5|pages=355–360|doi=10.3109/03009749709065698|issn=0300-9742|pmid=9385346}}</ref>

Women with these diseases may experiencing a worsening of symptoms at specific points in their menstrual cycle, particularly just before or around their periods.<ref>{{Cite journal|last=Zierau|first=Oliver|date=2012|title=Role of female sex hormones, estradiol and progesterone, in mast cell behavior|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377947/|journal=Front Immunol|volume=|pages=|via=}}</ref>

== Managing premenstrual symptoms ==

[[Nonsteroidal anti-inflammatory agents]] are occasionally effective in women with menstrual migraine, as are [[beta blockers]], [[calcium channel blocker]]s, [[ergotamine]], [[Antidepressant|antidepressant]]s, [[estrogen]] and [[estradiol]].<ref name=":2" />

== Pathophysiology of menstrual symptoms ==

[[Estrogen]] may directly affect [[blood vessel]]s by stimulating [[nitric oxide]] release. Women with a history of menstrual migraine had a heightened activation of the [[nitro oxide]] and [[L-arginine]] pathways, especially during the luteal phase.<ref>{{Cite journal|last=Brandes|first=Jan Lewis|date=2006-04-19|title=The Influence of Estrogen on Migraine: A Systematic Review|url=https://jamanetwork.com/journals/jama/fullarticle/202685|journal=JAMA|language=en|volume=295|issue=15|pages=1824–1830|doi=10.1001/jama.295.15.1824|issn=0098-7484}}</ref>

== Notable studies ==
* 2011, Gynecological History in Chronic Fatigue Syndrome: A Population-Based Case-Control Study<ref>{{Cite journal|last=Boneva|first=Roumiana S.|last2=Maloney|first2=Elizabeth M.|last3=Lin|first3=Jin-Mann|last4=Jones|first4=James F.|last5=Wieser|first5=Friedrich|last6=Nater|first6=Urs M.|last7=Heim|first7=Christine M.|last8=Reeves|first8=William C.|date=Jan 2011|title=Gynecological history in chronic fatigue syndrome: a population-based case-control study|url=https://www.ncbi.nlm.nih.gov/pubmed/21091051|journal=Journal of Women's Health (2002)|volume=20|issue=1|pages=21–28|doi=10.1089/jwh.2009.1900|issn=1931-843X|pmc=3017420|pmid=21091051|quote=|author-link=|author-link2=|author-link3=Jin-Mann Sally Lin|author-link4=|author-link5=|via=|author-link8=William Reeves}}</ref>

== See also ==

*[[Pregnancy]]
*[[Premenstrual syndrome]]

== References ==
<references />

[[Category:Triggers and risk factors]]