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{{Cleanup|reason=Some sections without references, plus more references needed | date = 2019}} Progesterone is a steroid and sex hormone that is created endogenously (by our own bodies) in the female reproduction organs, [[Adrenal gland|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.{{citation needed | date = Mar 2021}} === Progesterone vs. Progestins === ''Progestins'' is a general term for substances or medications that produce some or all of the effects of progesterone.<ref name="WebMD">{{Cite web|url=https://www.webmd.com/vitamins/ai/ingredientmono-760/progesterone| title = PROGESTERONE: Overview, Uses, Side Effects, Precautions, Interactions, Dosing and Reviews | last = | first = | author-link =| date = |website=WebMD|language=en|archive-url=|archive-date=|url-status=|access-date=2021-12-24}}</ref> 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.<ref name="WebMD" /> 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 increased risk of 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 web | 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|publisher=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 and 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 = | first = | website = Harvard Health Publishing|access-date=2019-08-08}}</ref><ref name="penn">{{Cite web|url=http://pennstatehershey.adam.com/content.aspx?productId=107&pid=33&gid=000280| title = Complementary and Alternative Medicine - Wild yam | website = Penn State Hershey Medical Center|access-date=2019-08-08}}</ref><ref>{{Cite bool|chapter=Chapter 17 - Soybean Oil Processing Byproducts and Their Utilization | date = 1995-01-01|url=https://www.sciencedirect.com/science/article/pii/B9780935315639500218|pages=297–313 | last = Woerfel | first = John B.|isbn=978-0-935315-63-9|language=en|publisher=AOCS Press | editor-last = Erickson | editor-first = David R. | title=Practical Handbook of Soybean Processing and Utilization}}</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 gland|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 book | 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 [[progestin]]s (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|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=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 name="H2014">{{Cite journal| title = Homeostasis Imbalance in the Endometrium of Women with Implantation Defects: The Role of Estrogen and Progesterone | date = Sep 2014|url=http://www.thieme-connect.de/DOI/DOI?10.1055/s-0034-1376355|journal=Seminars in Reproductive Medicine|volume=32|issue=05|pages=365–375 | last = Lessey | first = Bruce A. | author-link = | last2 = Young | first2 = Steven L. | authorlink2 = |language=en|doi=10.1055/s-0034-1376355|pmc=|pmid=|access-date=|issn=1526-8004|quote=|via=}}</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 name="H2014" /> 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 name="He2004">{{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 name="Nicola2013">{{Cite journal | last = Nicola | first=A. F. | last2 = De 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 of [[interleukin 6|IL-6]] and [[interleukin 8|IL-8]] in the inflammatory response to [[lipopolysaccharides]] in human uterine cervical fibroblasts.<ref>{{Cite journal| title = Anti-inflammatory effect of proteoglycan and progesterone on human uterine cervical fibroblasts | date = 2012-04-09|url=https://www.sciencedirect.com/science/article/pii/S0024320512000136|journal=Life Sciences|volume=90|issue=13 | pages = 484–488 | last = Fukuyama | first=Asami | last2 = Tanaka | first2 = Kanji | last3 = Kakizaki | first3 = Ikuko | last4 = Kasai | first4 = Kosuke | last5 = Chiba | first5 = Mitsuru | last6 = Nakamura | first6 = Toshiya | last7 = Mizunuma | first7 = Hideki|language=en|doi=10.1016/j.lfs.2011.12.024|issn=0024-3205}}</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 name="H2014" /> 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 name="H2014" /> ==== 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|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 [[Neuron|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 name="Nicola2013" /> 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 name="Kastrup1999">{{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 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 name="Kastrup1999" /> Research has also shown increased autonomic cardiac function in human females during the ovulation phase, when progesterone begins to rise rapidly.<ref name="Little1974">{{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 name="Fuenmayor2000">{{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 name="Little1974" /> Some medical experts believe low progesterone to estrogen ratios are often the source of [[Anxiety|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 name="Mahendroo2017">{{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 name="Eeckhout1992">{{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 = 3620888|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 [[Hypermobile EDS|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 name="PMC5020453">{{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: ==== Gynecological symptoms and prevalence of endometriosis==== {| class="wikitable" !Symptoms !''n'' (%) |- |Menorrhagia |292 (76) |- |Metrorrhagia |83 (22) |- |Dysmenorrhea |278 (72) |- |Deep dyspareuniea |118 (38) |- |Intromission dyspareuniea |148 (43) |- |Endometriosis |20 (6)<ref name="PMC5020453" /> |} ==== The influence of Hormones on hEDS Symptoms (hEDS Symptoms: Chronic Pain, Fatigue) ==== {| 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)<ref name="PMC5020453" /> |} <nowiki>*</nowiki>Combined hormonal contraceptives (estrogen and progestins) == See also == *[[Menstrual cycle]] *[[Pregnancy]] == References == {{Reflist}} [[Category:Neurotransmitters and hormones]] [[Category:Sex hormones]] [[Category:Hormones]]
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