Progesterone

<h2 id="biological-activity">Biological activity</h2>
See also: <a href="/facts/Pharmacodynamics_of_progesterone/8B7rNmS8">Pharmacodynamics of progesterone § Mechanism of action</a>
Progesterone is the most important progestogen in the body. As a potent <a href="/facts/Agonist/nz8U5NNp">agonist</a> of the <a href="/facts/Progesterone_receptor/B8W2o28f">nuclear progesterone receptor</a> (nPR) (with an <a href="/facts/Affinity_(pharmacology)/44QLL4eU">affinity</a> of KD = 1 nM) the resulting effects on ribosomal transcription plays a major role in regulation of female reproduction.<a class="footnote-ref" id="fnref:7" href="#fn:7">7</a><a class="footnote-ref" id="fnref:8" href="#fn:8">8</a> In addition, progesterone is an agonist of the more recently discovered <a href="/facts/Membrane_progesterone_receptor/I6osE3yk">membrane progesterone receptors</a> (mPRs),<a class="footnote-ref" id="fnref:9" href="#fn:9">9</a> of which the expression has regulation effects in reproduction function (<a href="/facts/Oocyte_maturation/4yHrJAwe">oocyte maturation</a>, labor, and <a href="/facts/Sperm_motility/PKHcbdjk">sperm motility</a>) and cancer although additional research is required to further define the roles.<a class="footnote-ref" id="fnref:10" href="#fn:10">10</a> It also functions as a ligand of the <a href="/facts/PGRMC1/d3xIr8fV">PGRMC1</a> (progesterone receptor membrane component 1) which impacts <a href="/facts/Tumor_progression/Y0wlbcQu">tumor progression</a>, metabolic regulation, and viability control of <a href="/facts/Nerve_cells/G7CyTVdH">nerve cells</a>.<a class="footnote-ref" id="fnref:11" href="#fn:11">11</a><a class="footnote-ref" id="fnref:12" href="#fn:12">12</a><a class="footnote-ref" id="fnref:13" href="#fn:13">13</a> Moreover, progesterone is also known to be an antagonist of the <a href="/facts/Sigma_receptor/JpFeF344">sigma</a> <a href="/facts/Sigma-1_receptor/qje6l9GW">σ1 receptor</a>,<a class="footnote-ref" id="fnref:14" href="#fn:14">14</a><a class="footnote-ref" id="fnref:15" href="#fn:15">15</a> a <a href="/facts/Negative_allosteric_modulator/Gg1It5Cj">negative allosteric modulator</a> of <a href="/facts/Nicotinic_acetylcholine_receptor/k2s2pPHr">nicotinic acetylcholine receptors</a>,<a class="footnote-ref" id="fnref:16" href="#fn:16">16</a> and a potent antagonist of the <a href="/facts/Mineralocorticoid_receptor/kwNhKIyC">mineralocorticoid receptor</a> (MR).<a class="footnote-ref" id="fnref:17" href="#fn:17">17</a> Progesterone prevents MR activation by binding to this receptor with an affinity exceeding even those of <a href="/facts/Aldosterone/tjw4dr1u">aldosterone</a> and <a href="/facts/Glucocorticoid/2P91Aj3S">glucocorticoids</a> such as <a href="/facts/Cortisol/5IvRV0cm">cortisol</a> and <a href="/facts/Corticosterone/rcMoEu7f">corticosterone</a>,<a class="footnote-ref" id="fnref:18" href="#fn:18">18</a> and produces <a href="/facts/Antimineralocorticoid/zbHHR8sT">antimineralocorticoid</a> effects, such as <a href="/facts/Natriuresis/FbQy3VXJ">natriuresis</a>, at physiological concentrations.<a class="footnote-ref" id="fnref:19" href="#fn:19">19</a> In addition, progesterone binds to and behaves as a <a href="/facts/Partial_agonist/VLm2vmgU">partial agonist</a> of the <a href="/facts/Glucocorticoid_receptor/NUsGokjq">glucocorticoid receptor</a> (GR), albeit with very low potency (<a href="/facts/EC50/x7oD7ITx">EC50</a> >100-fold less relative to <a href="/facts/Cortisol/5IvRV0cm">cortisol</a>).<a class="footnote-ref" id="fnref:20" href="#fn:20">20</a><a class="footnote-ref" id="fnref:21" href="#fn:21">21</a>
Progesterone, through its <a href="/facts/Neurosteroid/7YSfNqMR">neurosteroid</a> <a href="/facts/Active_metabolite/1zbPKbI0">active metabolites</a> such as <a href="/facts/5%25CE%25B1-dihydroprogesterone/Gck8NLjJ">5α-dihydroprogesterone</a> and <a href="/facts/Allopregnanolone/EgUYfpH2">allopregnanolone</a>, acts indirectly as a <a href="/facts/Positive_allosteric_modulator/Gg1It5Cj">positive allosteric modulator</a> of the <a href="/facts/GABAA_receptor/6G4rAGb3">GABAA receptor</a>.<a class="footnote-ref" id="fnref:22" href="#fn:22">22</a>
Progesterone and some of its metabolites, such as <a href="/facts/5%25CE%25B2-dihydroprogesterone/3M21y61W">5β-dihydroprogesterone</a>, are agonists of the <a href="/facts/Pregnane_X_receptor/cVYfQTcv">pregnane X receptor</a> (PXR),<a class="footnote-ref" id="fnref:23" href="#fn:23">23</a> albeit weakly so (<a href="/facts/EC50/x7oD7ITx">EC50</a> >10 μM).<a class="footnote-ref" id="fnref:24" href="#fn:24">24</a> In accordance, progesterone <a href="/facts/Enzyme_inducer/k3S7bhdA">induces</a> several <a href="/facts/Hepatic/Rtp4Fk2b">hepatic</a> <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450</a> <a href="/facts/Enzyme/DSI1Fh7y">enzymes</a>,<a class="footnote-ref" id="fnref:25" href="#fn:25">25</a> such as <a href="/facts/CYP3A4/MqD09gEj">CYP3A4</a>,<a class="footnote-ref" id="fnref:26" href="#fn:26">26</a><a class="footnote-ref" id="fnref:27" href="#fn:27">27</a> especially during <a href="/facts/Pregnancy/vEKYGpep">pregnancy</a> when concentrations are much higher than usual.<a class="footnote-ref" id="fnref:28" href="#fn:28">28</a> Perimenopausal women have been found to have greater CYP3A4 activity relative to men and postmenopausal women, and it has been inferred that this may be due to the higher progesterone levels present in perimenopausal women.<a class="footnote-ref" id="fnref:29" href="#fn:29">29</a>
Progesterone modulates the activity of <a href="/facts/Cation_channels_of_sperm/bsMhsoEd">CatSper</a> (cation channels of sperm) <a href="/facts/Voltage-gated_ion_channel/PwgWQn8s">voltage-gated</a> Ca2+ channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs (<a href="/facts/Chemotaxis/hYPRdPTk">chemotaxis</a>). As a result, it has been suggested that substances that block the progesterone binding site on CatSper channels could potentially be used in <a href="/facts/Male_contraception/emTQyKBs">male contraception</a>.<a class="footnote-ref" id="fnref:30" href="#fn:30">30</a><a class="footnote-ref" id="fnref:31" href="#fn:31">31</a>

<h2 id="biological-function">Biological function</h2>

<h3>Hormonal interactions</h3>
Progesterone has a number of physiological effects that are amplified in the presence of <a href="/facts/Estrogen/dPEewnDV">estrogens</a>. Estrogens through <a href="/facts/Estrogen_receptor/dEGaNney">estrogen receptors</a> (ERs) induce or <a href="/facts/Upregulation/6nRoa28r">upregulate</a> the <a href="/facts/Gene_expression/alCPohLR">expression</a> of the PR.<a class="footnote-ref" id="fnref:32" href="#fn:32">32</a> One example of this is in <a href="/facts/Breast/UBvcKAjy">breast</a> tissue, where estrogens allow progesterone to mediate <a href="/facts/Lobuloalveolar/f1omUfpN">lobuloalveolar</a> development.<a class="footnote-ref" id="fnref:33" href="#fn:33">33</a><a class="footnote-ref" id="fnref:34" href="#fn:34">34</a><a class="footnote-ref" id="fnref:35" href="#fn:35">35</a>
Elevated levels of progesterone potently reduce the sodium-retaining activity of aldosterone, resulting in natriuresis and a reduction in extracellular fluid volume. Progesterone withdrawal, on the other hand, is associated with a temporary increase in sodium retention (reduced natriuresis, with an increase in extracellular fluid volume) due to the compensatory increase in aldosterone production, which combats the blockade of the mineralocorticoid receptor by the previously elevated level of progesterone.<a class="footnote-ref" id="fnref:36" href="#fn:36">36</a>

<h3>Early sexual differentiation</h3>
<a href="/facts/Placenta/7XUoks1b">Placental</a> progesterone can be converted into <a href="/facts/5%25CE%25B1-dihydrotestosterone/fQpDuzcL">5α-dihydrotestosterone</a> (DHT), a potent <a href="/facts/Androgen/Rxey0HxX">androgen</a> that is responsible for the development of male genitalia.<a class="footnote-ref" id="fnref:37" href="#fn:37">37</a> This can be done both by conversion into testosterone, which is then converted to DHT, and via the <a href="/facts/Androgen_backdoor_pathway/pgqxQfUn">androgen backdoor pathway</a>, which is particularly important for <a href="/facts/Prenatal_development/VpV3S4lu">fetal development</a>.<a class="footnote-ref" id="fnref:38" href="#fn:38">38</a> As progesterone is the precursor for both pathways, it plays a key role in sexual differentiation.<a class="footnote-ref" id="fnref:39" href="#fn:39">39</a><a class="footnote-ref" id="fnref:40" href="#fn:40">40</a>

<h3>Reproductive system</h3>

Progesterone has key effects via non-genomic signalling on human sperm as they migrate through the female reproductive tract before <a href="/facts/Fertilization/g8u3UKzF">fertilization</a> occurs, though the receptor(s) as yet remain unidentified.<a class="footnote-ref" id="fnref:41" href="#fn:41">41</a> Detailed characterisation of the events occurring in sperm in response to progesterone has elucidated certain events including intracellular calcium transients and maintained changes,<a class="footnote-ref" id="fnref:42" href="#fn:42">42</a> slow calcium oscillations,<a class="footnote-ref" id="fnref:43" href="#fn:43">43</a> now thought to possibly regulate motility.<a class="footnote-ref" id="fnref:44" href="#fn:44">44</a> It is produced by the ovaries.<a class="footnote-ref" id="fnref:45" href="#fn:45">45</a> Progesterone has also been shown to demonstrate effects on octopus spermatozoa.<a class="footnote-ref" id="fnref:46" href="#fn:46">46</a>
Progesterone is sometimes called the "<a href="/facts/Pregnancy_hormones/1hE3yMdG">hormone of pregnancy</a>",<a class="footnote-ref" id="fnref:47" href="#fn:47">47</a> and it has many roles relating to the development of the fetus:

<ul><li>Progesterone converts the <a href="/facts/Endometrium/LcesXIXm">endometrium</a> to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the <a href="/facts/Vaginal_epithelium/xhujU1sT">vaginal epithelium</a> and <a href="/facts/Cervix/qw3gl8Pq">cervical mucus</a>, making it thick and impenetrable to <a href="/facts/Sperm/RCxpXygQ">sperm</a>. Progesterone is anti-<a href="/facts/Mitosis/ExxrSUs8">mitogenic</a> in endometrial epithelial cells, and as such, mitigates the tropic effects of <a href="/facts/Estrogen/dPEewnDV">estrogen</a>.<a class="footnote-ref" id="fnref:48" href="#fn:48">48</a> If <a href="/facts/Pregnancy/vEKYGpep">pregnancy</a> does not occur, progesterone levels will decrease, leading to <a href="/facts/Menstruate/7cv4HzLe">menstruation</a>. Normal menstrual bleeding is progesterone-withdrawal bleeding. If ovulation does not occur and the <a href="/facts/Corpus_luteum/rA91PnaC">corpus luteum</a> does not develop, levels of progesterone may be low, leading to <a href="/facts/Dysfunctional_uterine_bleeding/06n59DW5">anovulatory dysfunctional uterine bleeding.</a></li>
<li>During implantation and <a href="/facts/Gestation/QKgkykw5">gestation</a>, progesterone appears to decrease the maternal <a href="/facts/Immune_system/HRCTf1pb">immune</a> response to allow for the acceptance of the pregnancy.<a class="footnote-ref" id="fnref:49" href="#fn:49">49</a></li>
<li>Progesterone decreases contractility of the uterine <a href="/facts/Smooth_muscle/mpcpTsHp">smooth muscle</a>.<a class="footnote-ref" id="fnref:50" href="#fn:50">50</a> This effect contributes to prevention of <a href="/facts/Preterm_labor/szMos8tu">preterm labor</a>.<a class="footnote-ref" id="fnref:51" href="#fn:51">51</a> Studies have shown that in individuals who are pregnant with a single fetus, asymptomatic in the prenatal stage, and at a high risk of giving pre-term birth spontaneously, vaginal progesterone medication has been found to be effective in preventing spontaneous pre-term birth. Individuals who are at a high risk of giving pre-term birth spontaneously are those who have a short cervix of less than 25 mm or have previously given pre-term birth spontaneously. Although pre-term births are generally considered to be less than 37 weeks, these studies found that vaginal progesterone is associated with fewer pre-term births of less than 34 weeks.<a class="footnote-ref" id="fnref:52" href="#fn:52">52</a></li>
<li>A drop in progesterone levels is possibly one step that facilitates the onset of <a href="/facts/Labor_(childbirth)/KaWFJ4kG">labor</a>.</li>
<li>In addition, progesterone inhibits <a href="/facts/Lactation/0w1HoW27">lactation</a> during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production.</li></ul>
The <a href="/facts/Fetus/evocHd0Y">fetus</a> <a href="/facts/Metabolize/WxDrm8k5">metabolizes</a> placental progesterone in the production of <a href="/facts/Adrenal/3f8jV5aJ">adrenal</a> steroids.<a class="footnote-ref" id="fnref:53" href="#fn:53">53</a>

<h3>Breasts</h3>
See also: <a href="/facts/Breast_development/87L2NgV3">Breast development § Biochemistry</a>
<h4>Lobuloalveolar development</h4>
Progesterone plays an important role in <a href="/facts/Breast_development/87L2NgV3">breast development</a>. In conjunction with <a href="/facts/Prolactin/NcdqrzFU">prolactin</a>, it mediates <a href="/facts/Mammary_alveolus/f1omUfpN">lobuloalveolar</a> maturation of the <a href="/facts/Mammary_gland/6fVBnNSA">mammary glands</a> during pregnancy to allow for milk production and thus <a href="/facts/Lactation/0w1HoW27">lactation</a> and <a href="/facts/Breastfeeding/cdWXyYDX">breastfeeding</a> of <a href="/facts/Offspring/v7LD4qBl">offspring</a> following <a href="/facts/Parturition/1SSk6gMD">parturition</a> (childbirth).<a class="footnote-ref" id="fnref:54" href="#fn:54">54</a> <a href="/facts/Estrogen/dPEewnDV">Estrogen</a> induces expression of the PR in breast tissue and hence progesterone is dependent on estrogen to mediate lobuloalveolar development.<a class="footnote-ref" id="fnref:55" href="#fn:55">55</a><a class="footnote-ref" id="fnref:56" href="#fn:56">56</a><a class="footnote-ref" id="fnref:57" href="#fn:57">57</a> It has been found that <a href="/facts/Receptor_activator_of_nuclear_factor_kappa-B_ligand/bggQcUcm">RANKL</a>Tooltip Receptor activator of nuclear factor kappa-B ligand is a critical downstream mediator of progesterone-induced lobuloalveolar maturation.<a class="footnote-ref" id="fnref:58" href="#fn:58">58</a> RANKL <a href="/facts/Knockout_mice/Aw50cobf">knockout mice</a> show an almost identical mammary phenotype to PR knockout mice, including normal mammary ductal development but complete failure of the development of lobuloalveolar structures.<a class="footnote-ref" id="fnref:59" href="#fn:59">59</a>

<h4>Ductal development</h4>
Though to a far lesser extent than estrogen, which is the major mediator of mammary ductal development (via the <a href="/facts/Estrogen_receptor_alpha/PXU6tYY3">ERα</a>),<a class="footnote-ref" id="fnref:60" href="#fn:60">60</a><a class="footnote-ref" id="fnref:61" href="#fn:61">61</a> progesterone may be involved in ductal development of the mammary glands to some extent as well.<a class="footnote-ref" id="fnref:62" href="#fn:62">62</a> PR knockout mice or mice treated with the <a href="/facts/Antiprogestogen/W4dl9HJf">PR antagonist</a> <a href="/facts/Mifepristone/urGh3g00">mifepristone</a> show delayed although otherwise normal mammary ductal development at puberty.<a class="footnote-ref" id="fnref:63" href="#fn:63">63</a> In addition, mice modified to have <a href="/facts/Overexpression/N9yVF3lR">overexpression</a> of <a href="/facts/Progesterone_receptor_A/4gN8EHMQ">PRA</a> display ductal hyperplasia,<a class="footnote-ref" id="fnref:64" href="#fn:64">64</a> and progesterone induces ductal growth in the mouse mammary gland.<a class="footnote-ref" id="fnref:65" href="#fn:65">65</a> Progesterone mediates ductal development mainly via induction of the <a href="/facts/Gene_expression/alCPohLR">expression</a> of <a href="/facts/Amphiregulin/vCxJvlvD">amphiregulin</a>, the same <a href="/facts/Growth_factor/D1xnRbcH">growth factor</a> that estrogen primarily induces the expression of to mediate ductal development.<a class="footnote-ref" id="fnref:66" href="#fn:66">66</a> These animal findings suggest that, while not essential for full mammary ductal development, progesterone seems to play a potentiating or accelerating role in estrogen-mediated mammary ductal development.<a class="footnote-ref" id="fnref:67" href="#fn:67">67</a>

<h4>Breast cancer risk</h4>
Progesterone also appears to be involved in the <a href="/facts/Pathophysiology/Tp3Dny0c">pathophysiology</a> of <a href="/facts/Breast_cancer/6hME580v">breast cancer</a>, though its role, and whether it is a promoter or inhibitor of breast cancer risk, has not been fully elucidated.<a class="footnote-ref" id="fnref:68" href="#fn:68">68</a><a class="footnote-ref" id="fnref:69" href="#fn:69">69</a> Most <a href="/facts/Progestin/8xMJYV3A">progestins</a>, or <a href="/facts/Synthetic_compound/gqCNaN45">synthetic</a> progestogens, like <a href="/facts/Medroxyprogesterone_acetate/q6XACYYp">medroxyprogesterone acetate</a>, have been found to increase the risk of breast cancer in postmenopausal people in combination with estrogen as a component of <a href="/facts/Menopausal_hormone_therapy/d3KW80rn">menopausal hormone therapy</a>.<a class="footnote-ref" id="fnref:70" href="#fn:70">70</a><a class="footnote-ref" id="fnref:71" href="#fn:71">71</a> The combination of natural oral progesterone or the atypical progestin <a href="/facts/Dydrogesterone/GdG6dGrX">dydrogesterone</a> with estrogen has been associated with less risk of breast cancer than progestins plus estrogen.<a class="footnote-ref" id="fnref:72" href="#fn:72">72</a><a class="footnote-ref" id="fnref:73" href="#fn:73">73</a><a class="footnote-ref" id="fnref:74" href="#fn:74">74</a> However, this may simply be an artifact of the low progesterone levels produced with oral progesterone.<a class="footnote-ref" id="fnref:75" href="#fn:75">75</a><a class="footnote-ref" id="fnref:76" href="#fn:76">76</a> More research is needed on the role of progesterone in breast cancer.<a class="footnote-ref" id="fnref:77" href="#fn:77">77</a>

<h3>Skin health</h3>
The <a href="/facts/Estrogen_receptor/dEGaNney">estrogen receptor</a>, as well as the <a href="/facts/Progesterone_receptor/B8W2o28f">progesterone receptor</a>, have been detected in the <a href="/facts/Human_skin/cfRXQwSs">skin</a>, including in <a href="/facts/Keratinocyte/drqhJjuS">keratinocytes</a> and <a href="/facts/Fibroblast/n08KsFll">fibroblasts</a>.<a class="footnote-ref" id="fnref:78" href="#fn:78">78</a><a class="footnote-ref" id="fnref:79" href="#fn:79">79</a> At <a href="/facts/Menopause/b3Fz6NHb">menopause</a> and thereafter, decreased levels of female <a href="/facts/Sex_hormone/mI6bkHII">sex hormones</a> result in <a href="/facts/Atrophy/QNxSoxDV">atrophy</a>, thinning, and increased <a href="/facts/Wrinkling/qhLS2Lgb">wrinkling</a> of the skin and a reduction in skin <a href="/facts/Elasticity_(physics)/wcJoIFg1">elasticity</a>, firmness, and strength.<a class="footnote-ref" id="fnref:80" href="#fn:80">80</a><a class="footnote-ref" id="fnref:81" href="#fn:81">81</a> These skin changes constitute an acceleration in <a href="/facts/Human_skin/cfRXQwSs">skin aging</a> and are the result of decreased <a href="/facts/Collagen/KsyAb72K">collagen</a> content, irregularities in the <a href="/facts/Morphology_(biology)/Nl3B0myy">morphology</a> of <a href="/facts/Epidermis_(skin)/JvRABubP">epidermal</a> <a href="/facts/Skin_cell/4havlLzG">skin cells</a>, decreased <a href="/facts/Ground_substance/nvpvRF9e">ground substance</a> between <a href="/facts/Skin_fiber/AWMJ2KRj">skin fibers</a>, and reduced <a href="/facts/Capillary/4BIzKJAe">capillaries</a> and <a href="/facts/Blood_flow/HzubzJpn">blood flow</a>.<a class="footnote-ref" id="fnref:82" href="#fn:82">82</a><a class="footnote-ref" id="fnref:83" href="#fn:83">83</a> The skin also becomes more <a href="/facts/Dry_skin/kJLKYrNA">dry</a> during menopause, which is due to reduced skin <a href="/facts/Tissue_hydration/CXpnejT6">hydration</a> and <a href="/facts/Sebum/HKMXmv1Y">surface lipids</a> (sebum production).<a class="footnote-ref" id="fnref:84" href="#fn:84">84</a> Along with chronological aging and photoaging, estrogen deficiency in menopause is one of the three main factors that predominantly influences skin aging.<a class="footnote-ref" id="fnref:85" href="#fn:85">85</a>
Hormone replacement therapy, consisting of systemic treatment with estrogen alone or in combination with a progestogen, has well-documented and considerable beneficial effects on the skin of postmenopausal people.<a class="footnote-ref" id="fnref:86" href="#fn:86">86</a><a class="footnote-ref" id="fnref:87" href="#fn:87">87</a> These benefits include increased skin collagen content, skin thickness and elasticity, and skin hydration and surface lipids.<a class="footnote-ref" id="fnref:88" href="#fn:88">88</a><a class="footnote-ref" id="fnref:89" href="#fn:89">89</a> Topical estrogen has been found to have similar beneficial effects on the skin.<a class="footnote-ref" id="fnref:90" href="#fn:90">90</a> In addition, a study has found that topical 2% progesterone cream significantly increases skin elasticity and firmness and observably decreases wrinkles in peri- and postmenopausal people.<a class="footnote-ref" id="fnref:91" href="#fn:91">91</a> Skin hydration and surface lipids, on the other hand, did not significantly change with topical progesterone.<a class="footnote-ref" id="fnref:92" href="#fn:92">92</a>
These findings suggest that progesterone, like estrogen, also has beneficial effects on the skin, and may be independently protective against skin aging.<a class="footnote-ref" id="fnref:93" href="#fn:93">93</a>

<h3>Sexuality</h3>
<h4>Libido</h4>
See also: <a href="/facts/Sexual_motivation_and_hormones/mMXjWGpP">Sexual motivation and hormones</a>
Progesterone and its <a href="/facts/Neurosteroid/7YSfNqMR">neurosteroid</a> <a href="/facts/Active_metabolite/1zbPKbI0">active metabolite</a> <a href="/facts/Allopregnanolone/EgUYfpH2">allopregnanolone</a> appear to be importantly involved in <a href="/facts/Libido/jwxqvw1s">libido</a> in females.<a class="footnote-ref" id="fnref:94" href="#fn:94">94</a>

<h4>Homosexuality</h4>
Dr. <a href="/facts/Diana_Fleischman/Ko6nqYbr">Diana Fleischman</a>, of the <a href="/facts/University_of_Portsmouth/1UxPJ7KR">University of Portsmouth</a>, and colleagues looked for a relationship between progesterone and sexual attitudes in 92 women. Their research, published in the <a href="/facts/Archives_of_Sexual_Behavior/hzEcGgjQ">Archives of Sexual Behavior</a> found that women who had higher levels of progesterone scored higher on a questionnaire measuring homoerotic motivation. They also found that men who had high levels of progesterone were more likely to have higher homoerotic motivation scores after affiliative priming compared to men with low levels of progesterone.<a class="footnote-ref" id="fnref:95" href="#fn:95">95</a><a class="footnote-ref" id="fnref:96" href="#fn:96">96</a><a class="footnote-ref" id="fnref:97" href="#fn:97">97</a><a class="footnote-ref" id="fnref:98" href="#fn:98">98</a>

<h3>Nervous system</h3>
Progesterone, like <a href="/facts/Pregnenolone/VUPeSsgg">pregnenolone</a> and <a href="/facts/Dehydroepiandrosterone/djLk75uF">dehydroepiandrosterone</a> (DHEA), belongs to an important group of endogenous steroids called <a href="/facts/Neurosteroid/7YSfNqMR">neurosteroids</a>. It can be metabolized within all parts of the <a href="/facts/Central_nervous_system/k8I6To97">central nervous system</a>.<a class="footnote-ref" id="fnref:99" href="#fn:99">99</a>
Neurosteroids are <a href="/facts/Neuromodulator/mwjkrkHt">neuromodulators</a>, and are <a href="/facts/Neuroprotective/BcbsTfN0">neuroprotective</a>, <a href="/facts/Neurogenic/CDxRKU2U">neurogenic</a>, and regulate <a href="/facts/Neurotransmission/9H38LExu">neurotransmission</a> and <a href="/facts/Myelin/DKgJB8s8">myelination</a>.<a class="footnote-ref" id="fnref:100" href="#fn:100">100</a> The effects of progesterone as a neurosteroid are mediated predominantly through its interactions with non-nuclear PRs, namely the mPRs and <a href="/facts/PGRMC1/d3xIr8fV">PGRMC1</a>, as well as certain other receptors, such as the σ1 and nACh receptors.<a class="footnote-ref" id="fnref:101" href="#fn:101">101</a>

<h3>Brain damage</h3>
See also: <a href="/facts/Progesterone_(medication)/U3NtGBtS">Progesterone (medication) § Other uses</a>
Previous studies have shown that progesterone supports the normal development of neurons in the brain, and that the hormone has a protective effect on damaged brain tissue. It has been observed in animal models that females have reduced susceptibility to <a href="/facts/Traumatic_brain_injury/DTq110vw">traumatic brain injury</a> and this protective effect has been hypothesized to be caused by increased circulating levels of <a href="/facts/Estrogen/dPEewnDV">estrogen</a> and progesterone in females.<a class="footnote-ref" id="fnref:102" href="#fn:102">102</a>

<h4>Proposed mechanism</h4>
The mechanism of progesterone protective effects may be the reduction of inflammation that follows brain trauma and hemorrhage.<a class="footnote-ref" id="fnref:103" href="#fn:103">103</a><a class="footnote-ref" id="fnref:104" href="#fn:104">104</a>
Damage incurred by traumatic brain injury is believed to be caused in part by mass <a href="/facts/Depolarization/qGX8lFXE">depolarization</a> leading to <a href="/facts/Excitotoxicity/DKnHA79x">excitotoxicity</a>. One way in which progesterone helps to alleviate some of this excitotoxicity is by blocking the <a href="/facts/Voltage-dependent_calcium_channel/H9nAybJJ">voltage-dependent calcium channels</a> that trigger <a href="/facts/Neurotransmitter/LlpYFSU3">neurotransmitter</a> release.<a class="footnote-ref" id="fnref:105" href="#fn:105">105</a> It does so by manipulating the signaling pathways of <a href="/facts/Transcription_factor/wro0DPHe">transcription factors</a> involved in this release. Another method for reducing the excitotoxicity is by up-regulating the <a href="/facts/GABAA_receptor/6G4rAGb3">GABAA</a>, a widespread inhibitory neurotransmitter receptor.<a class="footnote-ref" id="fnref:106" href="#fn:106">106</a>
Progesterone has also been shown to prevent <a href="/facts/Apoptosis/8dVzSm4y">apoptosis</a> in neurons, a common consequence of brain injury. It does so by inhibiting enzymes involved in the apoptosis pathway specifically concerning the mitochondria, such as activated <a href="/facts/Caspase_3/FpjEwtwR">caspase 3</a> and <a href="/facts/Cytochrome_c/8gXbxw9z">cytochrome c</a>.<a class="footnote-ref" id="fnref:107" href="#fn:107">107</a>
Not only does progesterone help prevent further damage, it has also been shown to aid in <a href="/facts/Neuroregeneration/2wAxXAF2">neuroregeneration</a>.<a class="footnote-ref" id="fnref:108" href="#fn:108">108</a> One of the serious effects of traumatic brain injury includes edema. Animal studies show that progesterone treatment leads to a decrease in <a href="/facts/Edema/Q6MI3KdH">edema</a> levels by increasing the concentration of <a href="/facts/Macrophage/z7hkQu3o">macrophages</a> and <a href="/facts/Microglia/fU9dhL72">microglia</a> sent to the injured tissue.<a class="footnote-ref" id="fnref:109" href="#fn:109">109</a><a class="footnote-ref" id="fnref:110" href="#fn:110">110</a> This was observed in the form of reduced leakage from the <a href="/facts/Blood_brain_barrier/xYzvVwdu">blood brain barrier</a> in secondary recovery in progesterone treated rats. In addition, progesterone was observed to have <a href="/facts/Antioxidant/4TG4MQ83">antioxidant</a> properties, reducing the concentration of <a href="/facts/Reactive_oxygen_species/GpwSRugH">oxygen free radicals</a> faster than without.<a class="footnote-ref" id="fnref:111" href="#fn:111">111</a> There is also evidence that the addition of progesterone can also help re<a href="/facts/Myelin/DKgJB8s8">myelinate</a> damaged <a href="/facts/Axons/5DCd4wLo">axons</a> due to trauma, restoring some lost neural signal conduction.<a class="footnote-ref" id="fnref:112" href="#fn:112">112</a> Another way progesterone aids in regeneration includes increasing the circulation of endothelial progenitor cells in the brain. This helps new <a href="/facts/Vasculature/WXwudzzc">vasculature</a> to grow around scar tissue which helps repair the area of insult.<a class="footnote-ref" id="fnref:113" href="#fn:113">113</a>

<h3>Addiction</h3>
Progesterone enhances the function of <a href="/facts/Serotonin_receptor/D6656QzQ">serotonin receptors</a> in the brain, so an excess or deficit of progesterone has the potential to result in significant neurochemical issues. This provides an explanation for why some people resort to substances that enhance <a href="/facts/Serotonin/EzY58q4a">serotonin</a> activity such as <a href="/facts/Nicotine/VQ6HcIrY">nicotine</a>, <a href="/facts/Alcohol_(drug)/IeK2fVd5">alcohol</a>, and <a href="/facts/Cannabis_(drug)/241fYAGD">cannabis</a> when their progesterone levels fall below optimal levels.<a class="footnote-ref" id="fnref:114" href="#fn:114">114</a>

<ul><li>Sex differences in hormone levels may induce women to respond differently than men to nicotine. When women undergo cyclic changes or different hormonal transition phases (menopause, pregnancy, adolescence), there are changes in their progesterone levels.<a class="footnote-ref" id="fnref:115" href="#fn:115">115</a> Therefore, females have an increased biological vulnerability to nicotine's reinforcing effects compared to males and progesterone may be used to counter this enhanced vulnerability. This information supports the idea that progesterone can affect behavior.<a class="footnote-ref" id="fnref:116" href="#fn:116">116</a></li>
<li>Similar to nicotine, cocaine also increases the release of dopamine in the brain. The neurotransmitter is involved in the reward center and is one of the main neurotransmitters involved with substance abuse and reliance. In a study of cocaine users, it was reported that progesterone reduced craving and the feeling of being stimulated by cocaine. Thus, progesterone was suggested as an agent that decreases cocaine craving by reducing the dopaminergic properties of the drug.<a class="footnote-ref" id="fnref:117" href="#fn:117">117</a></li></ul>
<h3>Societal</h3>
In a 2012 University of Amsterdam study of 120 women, women's luteal phase (higher levels of progesterone, and increasing levels of estrogen) was correlated with a lower level of competitive behavior in gambling and math contest scenarios, while their premenstrual phase (sharply-decreasing levels of progesterone, and decreasing levels of estrogen) was correlated with a higher level of competitive behavior.<a class="footnote-ref" id="fnref:118" href="#fn:118">118</a>

<h3>Other effects</h3>
<ul><li>Progesterone also has a role in skin elasticity and bone strength, in <a href="/facts/Respiration_(physiology)/KKWAJIbd">respiration</a>, in nerve tissue and in <a href="/facts/Female_sexuality/6LLYGLPX">female sexuality</a>, and the presence of progesterone receptors in certain muscle and fat tissue may hint at a role in <a href="/facts/Sexual_dimorphism/nx9wulFy">sexually dimorphic</a> proportions of those.<a class="footnote-ref" id="fnref:119" href="#fn:119">119</a></li>
<li>During pregnancy, progesterone is said to decrease uterine irritability.<a class="footnote-ref" id="fnref:120" href="#fn:120">120</a></li>
<li>During pregnancy, progesterone helps to suppress immune responses of the mother to fetal antigens, which prevents rejection of the fetus.<a class="footnote-ref" id="fnref:121" href="#fn:121">121</a></li>
<li>Progesterone raises <a href="/facts/Epidermal_growth_factor-1/CpyH5tYs">epidermal growth factor-1</a> (EGF-1) levels, a factor often used to induce proliferation, and used to sustain cultures, of <a href="/facts/Stem_cell/qgB9dFrI">stem cells</a>.<a class="footnote-ref" id="fnref:122" href="#fn:122">122</a></li>
<li>Progesterone increases core temperature (thermogenic function) during ovulation.<a class="footnote-ref" id="fnref:123" href="#fn:123">123</a><a class="footnote-ref" id="fnref:124" href="#fn:124">124</a></li>
<li>Progesterone reduces <a href="/facts/Spasm/62EfFXKP">spasm</a> and relaxes <a href="/facts/Smooth_muscle/mpcpTsHp">smooth muscle</a>. <a href="/facts/Bronchi/t83cUXou">Bronchi</a> are widened and <a href="/facts/Mucus/hnlBuHAy">mucus</a> regulated. (PRs are widely present in <a href="/facts/Mucous_membrane/oIw0vyel">submucosal tissue</a>.)</li>
<li>Progesterone acts as an <a href="/facts/Inflammation/Ura86MIy">antiinflammatory</a> agent and regulates the <a href="/facts/Immune_response/dtLulqIy">immune response</a>.</li>
<li>Progesterone reduces <a href="/facts/Gall-bladder/RPdkQzQM">gall-bladder</a> activity.<a class="footnote-ref" id="fnref:125" href="#fn:125">125</a></li>
<li>Progesterone normalizes <a href="/facts/Blood/03zEulkj">blood</a> clotting and vascular tone, <a href="/facts/Zinc/80b1qgk3">zinc</a> and <a href="/facts/Copper/I8PEE8oX">copper</a> levels, <a href="/facts/Cell_(biology)/bLM9UQvy">cell</a> <a href="/facts/Oxygen/acyn6o8r">oxygen</a> levels, and use of fat stores for energy.</li>
<li>Progesterone may affect gum health, increasing risk of gingivitis (gum inflammation).<a class="footnote-ref" id="fnref:126" href="#fn:126">126</a></li>
<li>Progesterone appears to prevent <a href="/facts/Endometrial_cancer/rh605tHh">endometrial cancer</a> (involving the uterine lining) by regulating the effects of estrogen.</li>
<li>Progesterone plays an important role in the signaling of insulin release and pancreatic function, and may affect the susceptibility to diabetes or gestational diabetes.<a class="footnote-ref" id="fnref:127" href="#fn:127">127</a><a class="footnote-ref" id="fnref:128" href="#fn:128">128</a></li>
<li>Progesterone levels in the blood were found to be lower in those who had higher weight and higher BMI among those who became pregnant through in vitro fertilization.<a class="footnote-ref" id="fnref:129" href="#fn:129">129</a></li>
<li>Current data shows that micronized progesterone, which is chemically identical to the progesterone produced in people's bodies, in combination with estrogen in menopausal hormone therapy does not seem to have significant effects on venous thromboembolism (blood clots in veins) and ischemic stroke (lack of blood flow to the brain due to blockage of a blood vessel that supplies the brain). However, more studies need to be conducted to see whether or not micronized progesterone alone or in combined menopausal hormone therapy changes the risk of myocardial infarctions (heart attacks).<a class="footnote-ref" id="fnref:130" href="#fn:130">130</a></li>
<li>There have not been any studies done yet on the effects of micronized progesterone on hair loss due to menopause.<a class="footnote-ref" id="fnref:131" href="#fn:131">131</a></li>
<li>Despite suggestions for using hormone therapy to prevent loss of muscle mass in post-menopausal individuals (50 and older), menopausal hormone therapy involving either estrogen alone or estrogen and progesterone has not been found to preserve muscle mass.<a class="footnote-ref" id="fnref:132" href="#fn:132">132</a> Menopausal hormone therapy also does not result in body weight reduction, BMI reduction, or change in glucose metabolism.<a class="footnote-ref" id="fnref:133" href="#fn:133">133</a></li></ul>
<h2 id="biochemistry">Biochemistry</h2>
<h3>Biosynthesis</h3>

In mammals, progesterone, like all other <a href="/facts/Steroid/4AhMbgXt">steroid</a> <a href="/facts/Hormone/WFnBnINJ">hormones</a>, is synthesized from <a href="/facts/Pregnenolone/VUPeSsgg">pregnenolone</a>, which itself is derived from <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a>.
Cholesterol undergoes double oxidation to produce <a href="/facts/22R-hydroxycholesterol/7BClVsY0">22R-hydroxycholesterol</a> and then <a href="/facts/20%25CE%25B1%2c22R-dihydroxycholesterol/XDfX6kwb">20α,22R-dihydroxycholesterol</a>. This vicinal <a href="/facts/Diol/pmaVtfKx">diol</a> is then further oxidized with loss of the side chain starting at position C22 to produce pregnenolone. This reaction is catalyzed by <a href="/facts/Cytochrome/VF51IeGv">cytochrome</a> <a href="/facts/P450scc/fapmuxY6">P450scc</a>.
The conversion of pregnenolone to progesterone takes place in two steps. First, the 3β-<a href="/facts/Hydroxyl/1Hs2QAEv">hydroxyl</a> group is oxidized to a <a href="/facts/Ketone/BqQXpLo4">keto</a> group and second, the <a href="/facts/Double_bond/qDemMn0c">double bond</a> is moved to C4, from C5 through a keto/<a href="/facts/Enol/aySJNbQx">enol</a> <a href="/facts/Tautomer/ucdXGP9C">tautomerization</a> reaction.<a class="footnote-ref" id="fnref:134" href="#fn:134">134</a> This reaction is catalyzed by <a href="/facts/3%25CE%25B2-hydroxysteroid_dehydrogenase/UTLRwGCI">3β-hydroxysteroid dehydrogenase/δ5-4-isomerase</a>.
Progesterone in turn is the precursor of the mineralocorticoid <a href="/facts/Aldosterone/tjw4dr1u">aldosterone</a>, and after conversion to <a href="/facts/17%25CE%25B1-hydroxyprogesterone/RzVgaTaK">17α-hydroxyprogesterone</a>, of <a href="/facts/Cortisol/5IvRV0cm">cortisol</a> and <a href="/facts/Androstenedione/GBHxaQvQ">androstenedione</a>. Androstenedione can be converted to <a href="/facts/Testosterone/uUumdhAz">testosterone</a>, <a href="/facts/Estrone/FDbcmBGS">estrone</a>, and <a href="/facts/Estradiol/eCg3UCgX">estradiol</a>, highlighting the critical role of progesterone in testosterone synthesis.
Pregnenolone and progesterone can also be synthesized by <a href="/facts/Yeast/eGD24nfI">yeast</a>.<a class="footnote-ref" id="fnref:135" href="#fn:135">135</a>
Approximately 30 mg of progesterone is secreted from the ovaries per day in reproductive-age women, while the adrenal glands produce about 1 mg of progesterone per day.<a class="footnote-ref" id="fnref:136" href="#fn:136">136</a>

<ul><li>v</li><li>t</li><li>e</li></ul> Production rates, secretion rates, clearance rates, and blood levels of major sex hormones<table><tbody><tr><th rowspan="2">Sex</th><th rowspan="2">Sex hormone</th><th rowspan="2">Reproductivephase</th><th rowspan="2">Bloodproduction rate</th><th rowspan="2">Gonadalsecretion rate</th><th rowspan="2">Metabolicclearance rate</th><th colspan="2">Reference range (serum levels)</th></tr><tr><th>SI units</th><th>Non-SI units</th></tr><tr><td rowspan="5">Men</td><td><a href="/facts/Androstenedione/GBHxaQvQ">Androstenedione</a></td><td>–</td><td>2.8 mg/day</td><td>1.6 mg/day</td><td>2200 L/day</td><td>2.8–7.3 nmol/L</td><td>80–210 ng/dL</td></tr><tr><td><a href="/facts/Testosterone/uUumdhAz">Testosterone</a></td><td>–</td><td>6.5 mg/day</td><td>6.2 mg/day</td><td>950 L/day</td><td>6.9–34.7 nmol/L</td><td>200–1000 ng/dL</td></tr><tr><td><a href="/facts/Estrone/FDbcmBGS">Estrone</a></td><td>–</td><td>150 μg/day</td><td>110 μg/day</td><td>2050 L/day</td><td>37–250 pmol/L</td><td>10–70 pg/mL</td></tr><tr><td><a href="/facts/Estradiol/eCg3UCgX">Estradiol</a></td><td>–</td><td>60 μg/day</td><td>50 μg/day</td><td>1600 L/day</td><td><37–210 pmol/L</td><td>10–57 pg/mL</td></tr><tr><td><a href="/facts/Estrone_sulfate/7VhFxThx">Estrone sulfate</a></td><td>–</td><td>80 μg/day</td><td>Insignificant</td><td>167 L/day</td><td>600–2500 pmol/L</td><td>200–900 pg/mL</td></tr><tr><td rowspan="12">Women</td><td><a href="/facts/Androstenedione/GBHxaQvQ">Androstenedione</a></td><td>–</td><td>3.2 mg/day</td><td>2.8 mg/day</td><td>2000 L/day</td><td>3.1–12.2 nmol/L</td><td>89–350 ng/dL</td></tr><tr><td><a href="/facts/Testosterone/uUumdhAz">Testosterone</a></td><td>–</td><td>190 μg/day</td><td>60 μg/day</td><td>500 L/day</td><td>0.7–2.8 nmol/L</td><td>20–81 ng/dL</td></tr><tr><td rowspan="3"><a href="/facts/Estrone/FDbcmBGS">Estrone</a></td><td>Follicular phase</td><td>110 μg/day</td><td>80 μg/day</td><td>2200 L/day</td><td>110–400 pmol/L</td><td>30–110 pg/mL</td></tr><tr><td>Luteal phase</td><td>260 μg/day</td><td>150 μg/day</td><td>2200 L/day</td><td>310–660 pmol/L</td><td>80–180 pg/mL</td></tr><tr><td>Postmenopause</td><td>40 μg/day</td><td>Insignificant</td><td>1610 L/day</td><td>22–230 pmol/L</td><td>6–60 pg/mL</td></tr><tr><td rowspan="3"><a href="/facts/Estradiol/eCg3UCgX">Estradiol</a></td><td>Follicular phase</td><td>90 μg/day</td><td>80 μg/day</td><td>1200 L/day</td><td><37–360 pmol/L</td><td>10–98 pg/mL</td></tr><tr><td>Luteal phase</td><td>250 μg/day</td><td>240 μg/day</td><td>1200 L/day</td><td>699–1250 pmol/L</td><td>190–341 pg/mL</td></tr><tr><td>Postmenopause</td><td>6 μg/day</td><td>Insignificant</td><td>910 L/day</td><td><37–140 pmol/L</td><td>10–38 pg/mL</td></tr><tr><td rowspan="2"><a href="/facts/Estrone_sulfate/7VhFxThx">Estrone sulfate</a></td><td>Follicular phase</td><td>100 μg/day</td><td>Insignificant</td><td>146 L/day</td><td>700–3600 pmol/L</td><td>250–1300 pg/mL</td></tr><tr><td>Luteal phase</td><td>180 μg/day</td><td>Insignificant</td><td>146 L/day</td><td>1100–7300 pmol/L</td><td>400–2600 pg/mL</td></tr><tr><td rowspan="2">Progesterone</td><td>Follicular phase</td><td>2 mg/day</td><td>1.7 mg/day</td><td>2100 L/day</td><td>0.3–3 nmol/L</td><td>0.1–0.9 ng/mL</td></tr><tr><td>Luteal phase</td><td>25 mg/day</td><td>24 mg/day</td><td>2100 L/day</td><td>19–45 nmol/L</td><td>6–14 ng/mL</td></tr><tr><td colspan="8"></td></tr></tbody></table>
<h3>Distribution</h3>
Progesterone binds extensively to <a href="/facts/Plasma_protein/C87ptzI0">plasma proteins</a>, including <a href="/facts/Albumin/gDmSgAH2">albumin</a> (50–54%) and <a href="/facts/Transcortin/LSmKhvkA">transcortin</a> (43–48%).<a class="footnote-ref" id="fnref:137" href="#fn:137">137</a> It has similar affinity for albumin relative to the PR.<a class="footnote-ref" id="fnref:138" href="#fn:138">138</a>

<h3>Metabolism</h3>
The <a href="/facts/Metabolism/WxDrm8k5">metabolism</a> of progesterone is rapid and extensive and occurs mainly in the <a href="/facts/Liver/Rtp4Fk2b">liver</a>,<a class="footnote-ref" id="fnref:139" href="#fn:139">139</a><a class="footnote-ref" id="fnref:140" href="#fn:140">140</a><a class="footnote-ref" id="fnref:141" href="#fn:141">141</a> though <a href="/facts/Enzyme/DSI1Fh7y">enzymes</a> that metabolize progesterone are also expressed widely in the <a href="/facts/Brain/Xo5ABfXl">brain</a>, <a href="/facts/Skin/4havlLzG">skin</a>, and various other extrahepatic <a href="/facts/Tissue_(biology)/H7CpML7A">tissues</a>.<a class="footnote-ref" id="fnref:142" href="#fn:142">142</a><a class="footnote-ref" id="fnref:143" href="#fn:143">143</a> Progesterone has an <a href="/facts/Elimination_half-life/7nB2JtMr">elimination half-life</a> of only approximately 5 minutes in <a href="/facts/Circulatory_system/EGs6Y7sI">circulation</a>.<a class="footnote-ref" id="fnref:144" href="#fn:144">144</a> The metabolism of progesterone is complex, and it may form as many as 35 different <a href="/facts/Conjugation_(biochemistry)/WYyXtFIU">unconjugated</a> <a href="/facts/Metabolite/nAyywVtA">metabolites</a> when it is ingested orally.<a class="footnote-ref" id="fnref:145" href="#fn:145">145</a><a class="footnote-ref" id="fnref:146" href="#fn:146">146</a> Progesterone is highly susceptible to enzymatic <a href="/facts/Redox/Pyd5RVcj">reduction</a> via <a href="/facts/Reductase/R7ozNahQ">reductases</a> and <a href="/facts/Hydroxysteroid_dehydrogenase/kgEYBuP2">hydroxysteroid dehydrogenases</a> due to its <a href="/facts/Double_bond/qDemMn0c">double bond</a> (between the C4 and C5 positions) and its two <a href="/facts/Ketone/BqQXpLo4">ketones</a> (at the C3 and C20 positions).<a class="footnote-ref" id="fnref:147" href="#fn:147">147</a>
The major <a href="/facts/Metabolic_pathway/8Py8HKJd">metabolic pathway</a> of progesterone is reduction by <a href="/facts/5%25CE%25B1-reductase/kxzloQc3">5α-reductase</a><a class="footnote-ref" id="fnref:148" href="#fn:148">148</a> and <a href="/facts/5%25CE%25B2-reductase/lh36at1h">5β-reductase</a> into the dihydrogenated <a href="/facts/5%25CE%25B1-dihydroprogesterone/Gck8NLjJ">5α-dihydroprogesterone</a> and <a href="/facts/5%25CE%25B2-dihydroprogesterone/3M21y61W">5β-dihydroprogesterone</a>, respectively.<a class="footnote-ref" id="fnref:149" href="#fn:149">149</a><a class="footnote-ref" id="fnref:150" href="#fn:150">150</a><a class="footnote-ref" id="fnref:151" href="#fn:151">151</a><a class="footnote-ref" id="fnref:152" href="#fn:152">152</a> This is followed by the further reduction of these metabolites via <a href="/facts/3%25CE%25B1-hydroxysteroid_dehydrogenase/FK4cVy4b">3α-hydroxysteroid dehydrogenase</a> and <a href="/facts/3%25CE%25B2-hydroxysteroid_dehydrogenase/UTLRwGCI">3β-hydroxysteroid dehydrogenase</a> into the tetrahydrogenated <a href="/facts/Allopregnanolone/EgUYfpH2">allopregnanolone</a>, <a href="/facts/Pregnanolone/P54Kw9sc">pregnanolone</a>, <a href="/facts/Isopregnanolone/D8KHD8cN">isopregnanolone</a>, and <a href="/facts/Epipregnanolone/f470btVI">epipregnanolone</a>.<a class="footnote-ref" id="fnref:153" href="#fn:153">153</a><a class="footnote-ref" id="fnref:154" href="#fn:154">154</a><a class="footnote-ref" id="fnref:155" href="#fn:155">155</a><a class="footnote-ref" id="fnref:156" href="#fn:156">156</a> Subsequently, <a href="/facts/20%25CE%25B1-hydroxysteroid_dehydrogenase/b7c83boU">20α-hydroxysteroid dehydrogenase</a> and <a href="/facts/20%25CE%25B2-hydroxysteroid_dehydrogenase/DG19E5ra">20β-hydroxysteroid dehydrogenase</a> reduce these metabolites to form the corresponding hexahydrogenated <a href="/facts/Pregnanediol/mfWFYxxM">pregnanediols</a> (eight different <a href="/facts/Isomer/PXlvDVdg">isomers</a> in total),<a class="footnote-ref" id="fnref:157" href="#fn:157">157</a><a class="footnote-ref" id="fnref:158" href="#fn:158">158</a> which are then conjugated via <a href="/facts/Glucuronidation/G5qfwsFb">glucuronidation</a> and/or <a href="/facts/Sulfation/lI6B3Y1M">sulfation</a>, released from the liver into circulation, and <a href="/facts/Excretion/mspsTfnv">excreted</a> by the <a href="/facts/Kidney/HBspPrv9">kidneys</a> into the <a href="/facts/Urine/oNUYVtvX">urine</a>.<a class="footnote-ref" id="fnref:159" href="#fn:159">159</a><a class="footnote-ref" id="fnref:160" href="#fn:160">160</a> The major metabolite of progesterone in the urine is the 3α,5β,20α isomer of <a href="/facts/Pregnanediol_glucuronide/moLL6nln">pregnanediol glucuronide</a>, which has been found to constitute 15 to 30% of an injection of progesterone.<a class="footnote-ref" id="fnref:161" href="#fn:161">161</a><a class="footnote-ref" id="fnref:162" href="#fn:162">162</a> Other metabolites of progesterone formed by the enzymes in this pathway include <a href="/facts/3%25CE%25B1-dihydroprogesterone/FXsnVaya">3α-dihydroprogesterone</a>, <a href="/facts/3%25CE%25B2-dihydroprogesterone/oujqDCyg">3β-dihydroprogesterone</a>, <a href="/facts/20%25CE%25B1-dihydroprogesterone/oTzPa92M">20α-dihydroprogesterone</a>, and <a href="/facts/20%25CE%25B2-dihydroprogesterone/aWClWw4u">20β-dihydroprogesterone</a>, as well as various combination products of the enzymes aside from those already mentioned.<a class="footnote-ref" id="fnref:163" href="#fn:163">163</a><a class="footnote-ref" id="fnref:164" href="#fn:164">164</a><a class="footnote-ref" id="fnref:165" href="#fn:165">165</a><a class="footnote-ref" id="fnref:166" href="#fn:166">166</a> Progesterone can also first be <a href="/facts/Hydroxylation/AevYpR6L">hydroxylated</a> (see below) and then reduced.<a class="footnote-ref" id="fnref:167" href="#fn:167">167</a> Endogenous progesterone is metabolized approximately 50% into 5α-dihydroprogesterone in the <a href="/facts/Corpus_luteum/rA91PnaC">corpus luteum</a>, 35% into 3β-dihydroprogesterone in the liver, and 10% into 20α-dihydroprogesterone.<a class="footnote-ref" id="fnref:168" href="#fn:168">168</a>
Relatively small portions of progesterone are <a href="/facts/Hydroxylation/AevYpR6L">hydroxylated</a> via <a href="/facts/17%25CE%25B1-hydroxylase/MQcrtxpv">17α-hydroxylase</a> (CYP17A1) and <a href="/facts/21-hydroxylase/WUJ1b01V">21-hydroxylase</a> (CYP21A2) into <a href="/facts/17%25CE%25B1-hydroxyprogesterone/RzVgaTaK">17α-hydroxyprogesterone</a> and <a href="/facts/11-deoxycorticosterone/IA3xebF8">11-deoxycorticosterone</a> (21-hydroxyprogesterone), respectively,<a class="footnote-ref" id="fnref:169" href="#fn:169">169</a> and <a href="/facts/Pregnanetriol/oSqmoxzR">pregnanetriols</a> are formed secondarily to 17α-hydroxylation.<a class="footnote-ref" id="fnref:170" href="#fn:170">170</a><a class="footnote-ref" id="fnref:171" href="#fn:171">171</a> Even smaller amounts of progesterone may be also hydroxylated via <a href="/facts/11%25CE%25B2-hydroxylase/UNINEMj7">11β-hydroxylase</a> (CYP11B1) and to a lesser extent via <a href="/facts/Aldosterone_synthase/qnPvyP3T">aldosterone synthase</a> (CYP11B2) into <a href="/facts/11%25CE%25B2-hydroxyprogesterone/tGo6fufw">11β-hydroxyprogesterone</a>.<a class="footnote-ref" id="fnref:172" href="#fn:172">172</a><a class="footnote-ref" id="fnref:173" href="#fn:173">173</a><a class="footnote-ref" id="fnref:174" href="#fn:174">174</a> In addition, progesterone can be hydroxylated in the liver by other <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450</a> enzymes which are not steroid-specific.<a class="footnote-ref" id="fnref:175" href="#fn:175">175</a> 6β-Hydroxylation, which is catalyzed mainly by <a href="/facts/CYP3A4/MqD09gEj">CYP3A4</a>, is the major transformation, and is responsible for approximately 70% of cytochrome P450-mediated progesterone metabolism.<a class="footnote-ref" id="fnref:176" href="#fn:176">176</a> Other routes include 6α-, 16α-, and 16β-hydroxylation.<a class="footnote-ref" id="fnref:177" href="#fn:177">177</a> However, treatment of women with <a href="/facts/Ketoconazole/UQcvnER5">ketoconazole</a>, a strong CYP3A4 inhibitor, had minimal effects on progesterone levels, producing only a slight and non-significant increase, and this suggests that cytochrome P450 enzymes play only a small role in progesterone metabolism.<a class="footnote-ref" id="fnref:178" href="#fn:178">178</a>

<table><tbody><tr><td><ul><li>v</li><li>t</li><li>e</li></ul> <a href="/facts/Metabolic_pathway/8Py8HKJd">Metabolism</a> of progesterone in humans<a class="footnote-ref" id="fnref:179" href="#fn:179">179</a> Progesterone<a href="/facts/17%25CE%25B1-Hydroxyprogesterone/RzVgaTaK">17α-Hydroxyprogesterone</a><a href="/facts/11-Deoxycorticosterone/IA3xebF8">11-Deoxycorticosterone</a><a href="/facts/Pregnanetriols/oSqmoxzR">Pregnanetriols</a>(8 isomers)<a href="/facts/5%25CE%25B1-Dihydroprogesterone/Gck8NLjJ">5α-Dihydroprogesterone</a><a href="/facts/5%25CE%25B2-Dihydroprogesterone/3M21y61W">5β-Dihydroprogesterone</a><a href="/facts/Allopregnanolone/EgUYfpH2">Allopregnanolone</a><a href="/facts/Isopregnanolone/D8KHD8cN">Isopregnanolone</a><a href="/facts/Pregnanolone/P54Kw9sc">Pregnanolone</a><a href="/facts/Epipregnanolone/f470btVI">Epipregnanolone</a><a href="/facts/Pregnanediols/qfTvWT5o">Pregnanediols</a>(8 isomers)<a href="/facts/17%25CE%25B1-Hydroxylase/MQcrtxpv">17α-Hydroxylase</a><a href="/facts/21-Hydroxylase/WUJ1b01V">21-Hydroxylase</a>Multiple<a href="/facts/5%25CE%25B1-Reductase/kxzloQc3">5α-Reductase</a><a href="/facts/5%25CE%25B2-Reductase/lh36at1h">5β-Reductase</a><a href="/facts/3%25CE%25B1-Hydroxysteroid_dehydrogenase/FK4cVy4b">3α-HSD</a><a href="/facts/3%25CE%25B2-Hydroxysteroid_dehydrogenase/UTLRwGCI">3β-HSD</a><a href="/facts/3%25CE%25B1-Hydroxysteroid_dehydrogenase/FK4cVy4b">3α-HSD</a><a href="/facts/3%25CE%25B2-Hydroxysteroid_dehydrogenase/UTLRwGCI">3β-HSD</a><a href="/facts/20%25CE%25B1-Hydroxysteroid_dehydrogenase/b7c83boU">20α-HSD</a><a href="/facts/20%25CE%25B2-Hydroxysteroid_dehydrogenase/DG19E5ra">20β-HSD</a>This diagram illustrates the <a href="/facts/Metabolic_pathway/8Py8HKJd">metabolic pathways</a> involved in the <a href="/facts/Metabolism/WxDrm8k5">metabolism</a> of progesterone in humans. In addition to the <a href="/facts/Biotransformation/WYyXtFIU">transformations</a> shown in the diagram, <a href="/facts/Conjugation_(biochemistry)/WYyXtFIU">conjugation</a>, specifically <a href="/facts/Glucuronidation/G5qfwsFb">glucuronidation</a> and <a href="/facts/Sulfation/lI6B3Y1M">sulfation</a>, occurs with <a href="/facts/Metabolite/nAyywVtA">metabolites</a> of progesterone that have one or more available <a href="/facts/Hydroxyl_group/1Hs2QAEv">hydroxyl</a> (–OH) <a href="/facts/Functional_group/GXkSPsjM">groups</a>.</td></tr></tbody></table>

<h3>Levels</h3>

Progesterone levels are relatively low during the preovulatory phase of the <a href="/facts/Menstrual_cycle/AY6Y9xxM">menstrual cycle</a>, rise after <a href="/facts/Ovulation/0K3MLdAv">ovulation</a>, and are elevated during the <a href="/facts/Luteal_phase/R9rpFdKT">luteal phase</a>, as shown in the diagram above. Progesterone levels tend to be less than 2 ng/mL prior to ovulation and greater than 5 ng/mL after ovulation. If <a href="/facts/Pregnancy/vEKYGpep">pregnancy</a> occurs, <a href="/facts/Human_chorionic_gonadotropin/AKeIq9nd">human chorionic gonadotropin</a> is released, maintaining the corpus luteum and allowing it to maintain levels of progesterone. Between 7 and 9 weeks, the placenta begins to produce progesterone in place of the corpus luteum in a process called the luteal-placental shift.<a class="footnote-ref" id="fnref:180" href="#fn:180">180</a>
After the luteal-placental shift, progesterone levels start to rise further and may reach 100 to 200 ng/mL at term. Whether a decrease in progesterone levels is critical for the initiation of <a href="/facts/Labor_(childbirth)/KaWFJ4kG">labor</a> has been argued and may be species-specific. After delivery of the placenta and during lactation, progesterone levels are very low.
Progesterone levels are low in children and postmenopausal people.<a class="footnote-ref" id="fnref:181" href="#fn:181">181</a> Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.

Endogenous <a href="/facts/Progesterone_(medication)/U3NtGBtS">progesterone</a> production rates and plasma progesterone levels<table><tbody><tr><th>Group</th><th>P4 production</th><th>P4 levels</th></tr><tr><td><a href="/facts/Prepuberty/3sImdgGL">Prepubertal</a> children</td><td>ND</td><td>0.06–0.5 ng/mL</td></tr><tr><td><a href="/facts/Puberty/vjfPAKf4">Pubertal</a> girls  <a href="/facts/Tanner_scale/bKIJ5xk4">Tanner stage I</a> (childhood)  <a href="/facts/Tanner_scale/bKIJ5xk4">Tanner stage II</a> (ages 8–12)  <a href="/facts/Tanner_scale/bKIJ5xk4">Tanner stage III</a> (ages 10–13)  <a href="/facts/Tanner_scale/bKIJ5xk4">Tanner stage IV</a> (ages 11–14)  <a href="/facts/Tanner_scale/bKIJ5xk4">Tanner stage V</a> (ages 12–15)    <a href="/facts/Follicular_phase/dHsuajWd">Follicular phase</a> (days 1–14)    <a href="/facts/Luteal_phase/R9rpFdKT">Luteal phase</a> (days 15–28)</td><td> NDNDNDND NDND</td><td> 0.22 (<0.10–0.32) ng/mL0.30 (0.10–0.51) ng/mL0.36 (0.10–0.75) ng/mL1.75 (<0.10–25.0) ng/mL 0.35 (0.13–0.75) ng/mL2.0–25.0 ng/mL</td></tr><tr><td><a href="/facts/Premenopause/b3Fz6NHb">Premenopausal</a> women  <a href="/facts/Follicular_phase/dHsuajWd">Follicular phase</a> (days 1–14)  <a href="/facts/Luteal_phase/R9rpFdKT">Luteal phase</a> (days 15–28)  <a href="/facts/Oral_contraceptive/QfDgVrGA">Oral contraceptive</a> (<a href="/facts/Anovulation/nbg5Speh">anovulatory</a>)</td><td> 0.75–5.4 mg/day15–50 mg/dayND</td><td> 0.02–1.2 ng/mL4–30 ng/mL0.1–0.3 ng/mL</td></tr><tr><td><a href="/facts/Menopause/b3Fz6NHb">Postmenopausal</a> women<a href="/facts/Oophorectomy/npGMfV5u">Oophorectomized</a> women<a href="/facts/Oophorectomy/npGMfV5u">Oophorectomized</a> and <a href="/facts/Adrenalectomy/m3jVcenl">adrenalectomized</a> women</td><td>ND1.2 mg/day<0.3 mg/day</td><td>0.03–0.3 ng/mL0.39 ng/mLND</td></tr><tr><td><a href="/facts/Pregnancy/vEKYGpep">Pregnant</a> women  <a href="/facts/First_trimester/vEKYGpep">First trimester</a> (weeks 1–12)  <a href="/facts/Second_trimester/vEKYGpep">Second trimester</a> (weeks 13–26)  <a href="/facts/Third_trimester/vEKYGpep">Third trimester</a> (weeks 27–40)  <a href="/facts/Postpartum/abLj2JtY">Postpartum</a> (at 24 hours)</td><td> 55 mg/day92–100 mg/day190–563 mg/dayND</td><td> 9–75 ng/mL17–146 ng/mL55–255 ng/mL19 ng/mL</td></tr><tr><td>Men</td><td>0.75–3 mg/day</td><td>0.1–0.3 ng/mL</td></tr><tr><td colspan="5">Notes: Mean levels are given as a single value and ranges are given after in parentheses. Sources: <a class="footnote-ref" id="fnref:182" href="#fn:182">182</a><a class="footnote-ref" id="fnref:183" href="#fn:183">183</a><a class="footnote-ref" id="fnref:184" href="#fn:184">184</a><a class="footnote-ref" id="fnref:185" href="#fn:185">185</a><a class="footnote-ref" id="fnref:186" href="#fn:186">186</a><a class="footnote-ref" id="fnref:187" href="#fn:187">187</a><a class="footnote-ref" id="fnref:188" href="#fn:188">188</a><a class="footnote-ref" id="fnref:189" href="#fn:189">189</a><a class="footnote-ref" id="fnref:190" href="#fn:190">190</a></td></tr></tbody></table>
<h4>Ranges</h4>
Blood test results should always be interpreted using the reference ranges provided by the laboratory that performed the results. Example reference ranges are listed below.

<table><tbody><tr><th rowspan="2">Person type</th><th colspan="3"><a href="/facts/Reference_range_for_blood_test/Fls5Gbtb">Reference range for blood test</a></th></tr><tr><th>Lower limit</th><th>Upper limit</th><th>Unit</th></tr><tr><td>Female - menstrual cycle</td><td colspan="3">(see diagram below)</td></tr><tr><td rowspan="2">Female - postmenopausal</td><td><a href="/facts/Less_than/qkze4zdI"><</a>0.2<a class="footnote-ref" id="fnref:191" href="#fn:191">191</a></td><td>1<a class="footnote-ref" id="fnref:192" href="#fn:192">192</a></td><td><a href="/facts/Nanogram/2jIXpAFv">ng</a>/<a href="/facts/Millilitre/QKwbQz8I">mL</a></td></tr><tr><td><0.6<a class="footnote-ref" id="fnref:193" href="#fn:193">193</a></td><td>3<a class="footnote-ref" id="fnref:194" href="#fn:194">194</a></td><td><a href="/facts/Nanomole/kCMFwCc0">nmol</a>/<a href="/facts/Litre/QKwbQz8I">L</a></td></tr><tr><td rowspan="2">Female on <a href="/facts/Oral_contraceptive/QfDgVrGA">oral contraceptives</a></td><td>0.34<a class="footnote-ref" id="fnref:195" href="#fn:195">195</a></td><td>0.92<a class="footnote-ref" id="fnref:196" href="#fn:196">196</a></td><td>ng/mL</td></tr><tr><td>1.1<a class="footnote-ref" id="fnref:197" href="#fn:197">197</a></td><td>2.9<a class="footnote-ref" id="fnref:198" href="#fn:198">198</a></td><td>nmol/L</td></tr><tr><td rowspan="2">Males <a href="/facts/Greater_than_or_equal_to/qkze4zdI">≥</a>16 years</td><td>0.27<a class="footnote-ref" id="fnref:199" href="#fn:199">199</a></td><td>0.9<a class="footnote-ref" id="fnref:200" href="#fn:200">200</a></td><td>ng/mL</td></tr><tr><td>0.86<a class="footnote-ref" id="fnref:201" href="#fn:201">201</a></td><td>2.9<a class="footnote-ref" id="fnref:202" href="#fn:202">202</a></td><td>nmol/L</td></tr><tr><td rowspan="2">Female or male 1–9 years</td><td>0.1<a class="footnote-ref" id="fnref:203" href="#fn:203">203</a></td><td>4.1<a class="footnote-ref" id="fnref:204" href="#fn:204">204</a> or 4.5<a class="footnote-ref" id="fnref:205" href="#fn:205">205</a></td><td>ng/mL</td></tr><tr><td>0.3<a class="footnote-ref" id="fnref:206" href="#fn:206">206</a></td><td>13<a class="footnote-ref" id="fnref:207" href="#fn:207">207</a></td><td>nmol/L</td></tr></tbody></table>

<h3>Sources</h3>
<h4>Animal</h4>
Progesterone is produced in high amounts in the <a href="/facts/Ovaries/z2hG6bNy">ovaries</a> (by the <a href="/facts/Corpus_luteum/rA91PnaC">corpus luteum</a>) from the onset of <a href="/facts/Puberty/vjfPAKf4">puberty</a> to <a href="/facts/Menopause/b3Fz6NHb">menopause</a>, and is also produced in smaller amounts by the <a href="/facts/Adrenal_gland/3f8jV5aJ">adrenal glands</a> after the onset of <a href="/facts/Adrenarche/r2pp76DV">adrenarche</a> in both males and females. To a lesser extent, progesterone is produced in <a href="/facts/Nervous_tissue/YY7qG0WD">nervous tissue</a>, especially in the brain, and in <a href="/facts/Adipose_tissue/PxxedB6e">adipose (fat) tissue</a>, as well.
During human <a href="/facts/Pregnancy/vEKYGpep">pregnancy</a>, progesterone is produced in increasingly high amounts by the ovaries and <a href="/facts/Placenta/7XUoks1b">placenta</a>. At first, the source is the corpus luteum that has been "rescued" by the presence of <a href="/facts/Human_chorionic_gonadotropin/AKeIq9nd">human chorionic gonadotropin</a> (hCG) from the conceptus. However, after the 8th week, production of progesterone shifts to the placenta. The placenta utilizes maternal cholesterol as the initial substrate, and most of the produced progesterone enters the maternal circulation, but some is picked up by the fetal circulation and used as substrate for fetal corticosteroids. At term the placenta produces about 250 mg progesterone per day.
An additional animal source of progesterone is milk products. After consumption of milk products the level of bioavailable progesterone goes up.<a class="footnote-ref" id="fnref:208" href="#fn:208">208</a>

<h4>Plants</h4>
In at least one plant, <a href="/facts/Juglans_regia/aJKt0VKp">Juglans regia</a>, progesterone has been detected.<a class="footnote-ref" id="fnref:209" href="#fn:209">209</a> In addition, progesterone-like <a href="/facts/Steroid/4AhMbgXt">steroids</a> are found in <a href="/facts/Dioscorea_mexicana/NJsI79rj">Dioscorea mexicana</a>. Dioscorea mexicana is a plant that is part of the <a href="/facts/Yam_(vegetable)/b0E3kuD1">yam</a> family native to <a href="/facts/Mexico/IT5bwhdh">Mexico</a>.<a class="footnote-ref" id="fnref:210" href="#fn:210">210</a> It contains a steroid called <a href="/facts/Diosgenin/Q5mTgo0f">diosgenin</a> that is taken from the plant and is converted into progesterone.<a class="footnote-ref" id="fnref:211" href="#fn:211">211</a> Diosgenin and progesterone are also found in other <a href="/facts/Dioscorea/0cg8rwBu">Dioscorea</a> species, as well as in other plants that are not closely related, such as <a href="/facts/Fenugreek/1BKUXEwj">fenugreek</a>.
Another plant that contains substances readily convertible to progesterone is <a href="/facts/Dioscorea_pseudojaponica/0cg8rwBu">Dioscorea pseudojaponica</a> native to <a href="/facts/Taiwan/VcJoUD8w">Taiwan</a>. Research has shown that the Taiwanese yam contains <a href="/facts/Saponin/0cqUdnJM">saponins</a> — steroids that can be converted to diosgenin and thence to progesterone.<a class="footnote-ref" id="fnref:212" href="#fn:212">212</a>
Many other Dioscorea species of the yam family contain steroidal substances from which progesterone can be produced. Among the more notable of these are <a href="/facts/Dioscorea_villosa/Bj3Y7Uzz">Dioscorea villosa</a> and <a href="/facts/Dioscorea_polygonoides/0cg8rwBu">Dioscorea polygonoides</a>. One study showed that the Dioscorea villosa contains 3.5% diosgenin.<a class="footnote-ref" id="fnref:213" href="#fn:213">213</a> <a href="/facts/Dioscorea_polygonoides/0cg8rwBu">Dioscorea polygonoides</a> has been found to contain 2.64% diosgenin as shown by <a href="/facts/Gas_chromatography-mass_spectrometry/Gm3eCCoQ">gas chromatography-mass spectrometry</a>.<a class="footnote-ref" id="fnref:214" href="#fn:214">214</a> Many of the Dioscorea species that originate from the yam family grow in countries that have tropical and subtropical climates.<a class="footnote-ref" id="fnref:215" href="#fn:215">215</a>

<h2 id="medical-use">Medical use</h2>
Main articles: <a href="/facts/Progesterone_(medication)/U3NtGBtS">Progesterone (medication)</a>, <a href="/facts/Pharmacodynamics_of_progesterone/8B7rNmS8">Pharmacodynamics of progesterone</a>, and <a href="/facts/Pharmacokinetics_of_progesterone/nY6CqbFT">Pharmacokinetics of progesterone</a>
Progesterone is used as a <a href="/facts/Medication/h9mhwWP2">medication</a>. It is used in combination with <a href="/facts/Estrogen_(medication)/mSKFraNu">estrogens</a> mainly in <a href="/facts/Hormone_replacement_therapy/d3KW80rn">hormone therapy</a> for <a href="/facts/Menopause/b3Fz6NHb">menopausal</a> <a href="/facts/Symptom/BzP6MrTN">symptoms</a> and <a href="/facts/Hypogonadism/mqu59lNo">low sex hormone levels</a>.<a class="footnote-ref" id="fnref:216" href="#fn:216">216</a><a class="footnote-ref" id="fnref:217" href="#fn:217">217</a> It may also be used alone to treat menopausal symptoms. Studies have shown that transdermal progesterone (skin patch) and oral micronized progesterone are effective treatments for certain symptoms of menopause such as hot flashes and night sweats, which are otherwise referred to as vasomotor symptoms or VMS.<a class="footnote-ref" id="fnref:218" href="#fn:218">218</a>
It is also used to support <a href="/facts/Pregnancy/vEKYGpep">pregnancy</a> and <a href="/facts/Fertility/5S7Xull5">fertility</a> and to treat <a href="/facts/Gynecological_disorder/KKAAAcnb">gynecological disorders</a>.<a class="footnote-ref" id="fnref:219" href="#fn:219">219</a><a class="footnote-ref" id="fnref:220" href="#fn:220">220</a><a class="footnote-ref" id="fnref:221" href="#fn:221">221</a><a class="footnote-ref" id="fnref:222" href="#fn:222">222</a> Progesterone has been shown to prevent miscarriage in those with 1) vaginal bleeding early in their current pregnancy and 2) a previous history of miscarriage.<a class="footnote-ref" id="fnref:223" href="#fn:223">223</a> Progesterone can be taken <a href="/facts/Oral_administration/vNQcvLVx">by mouth</a>, <a href="/facts/Intravaginal_administration/kIwGRMDf">through the vagina</a>, and by <a href="/facts/Injection_(medicine)/fvkH58gk">injection</a> into <a href="/facts/Muscle/dmxrL8pH">muscle</a> or <a href="/facts/Fat/87HcP11s">fat</a>, among other <a href="/facts/Route_of_administration/LsyoHTzH">routes</a>.<a class="footnote-ref" id="fnref:224" href="#fn:224">224</a>

<h2 id="chemistry">Chemistry</h2>

See also: <a href="/facts/List_of_neurosteroids/6dWIMHhF">List of neurosteroids</a>
Progesterone is a <a href="/facts/Natural_product/J4RsVhmP">naturally occurring</a> <a href="/facts/Pregnane/tbXV6N95">pregnane</a> <a href="/facts/Steroid/4AhMbgXt">steroid</a> and is also known as pregn-4-ene-3,20-dione.<a class="footnote-ref" id="fnref:225" href="#fn:225">225</a><a class="footnote-ref" id="fnref:226" href="#fn:226">226</a> It has a <a href="/facts/Double_bond/qDemMn0c">double bond</a> (<a href="/facts/-ene/GF7l4quC">4-ene</a>) between the C4 and C5 positions and two <a href="/facts/Ketone/BqQXpLo4">ketone</a> <a href="/facts/Functional_group/GXkSPsjM">groups</a> (3,20-<a href="/facts/Diketone/JbdbaftY">dione</a>), one at the C3 position and the other at the C20 position.<a class="footnote-ref" id="fnref:227" href="#fn:227">227</a><a class="footnote-ref" id="fnref:228" href="#fn:228">228</a>

<h3>Synthesis</h3>
Progesterone is commercially produced by semisynthesis. Two main routes are used: one from yam <a href="/facts/Diosgenin/Q5mTgo0f">diosgenin</a> first pioneered by Marker in 1940, and one based on soy <a href="/facts/Phytosterol/W3RMbnfK">phytosterols</a> scaled up in the 1970s. Additional (not necessarily economical) semisyntheses of progesterone have also been reported starting from a variety of steroids. For the example, <a href="/facts/Cortisone/z5GUmvNG">cortisone</a> can be simultaneously deoxygenated at the C-17 and C-21 position by treatment with iodotrimethylsilane in <a href="/facts/Chloroform/gvzuJMXa">chloroform</a> to produce 11-keto-progesterone (ketogestin), which in turn can be reduced at position-11 to yield progesterone.<a class="footnote-ref" id="fnref:229" href="#fn:229">229</a>

<h4>Marker semisynthesis</h4>
Main article: <a href="/facts/Marker_degradation/mkKcfdCM">Marker degradation</a>
An economical <a href="/facts/Semisynthesis/nEMoPxhv">semisynthesis</a> of progesterone from the plant steroid <a href="/facts/Diosgenin/Q5mTgo0f">diosgenin</a> isolated from yams was developed by <a href="/facts/Russell_Earl_Marker/g6hWAgHc">Russell Marker</a> in 1940 for the <a href="/facts/Parke-Davis/HhJ7hzUW">Parke-Davis</a> pharmaceutical company.<a class="footnote-ref" id="fnref:230" href="#fn:230">230</a> This synthesis is known as the <a href="/facts/Marker_degradation/mkKcfdCM">Marker degradation</a>.

The <a href="/facts/16-DPA/qk7QFBkm">16-DPA</a> intermediate is important to the synthesis of many other medically important steroids. A very similar approach can produce 16-DPA from <a href="/facts/Solanine/Iwxa3UI5">solanine</a>.<a class="footnote-ref" id="fnref:231" href="#fn:231">231</a>

<h4>Soy semisynthesis</h4>
Progesterone can also be made from the <a href="/facts/Stigmasterol/At001R9e">stigmasterol</a> found in <a href="/facts/Soybean_oil/I9NzorzT">soybean oil</a> also. c.f. <a href="/facts/Percy_Julian/7xQ0Qe1q">Percy Julian</a>.

<h4>Total synthesis</h4>

A <a href="/facts/Total_synthesis/3GGoqhBm">total synthesis</a> of progesterone was reported in 1971 by <a href="/facts/William_Summer_Johnson/eKly8FME">W.S. Johnson</a>.<a class="footnote-ref" id="fnref:232" href="#fn:232">232</a> The synthesis begins with reacting the <a href="/facts/Phosphonium_salt/uS2PCt7X">phosphonium salt</a> 7 with <a href="/facts/Organolithium_reagent/xgYnjhP3">phenyl lithium</a> to produce the <a href="/facts/Phosphonium_ylide/7Cjao2HI">phosphonium ylide</a> 8. The ylide 8 is reacted with an <a href="/facts/Aldehyde/xSIRkW03">aldehyde</a> to produce the <a href="/facts/Alkene/RtYcS6kU">alkene</a> 9. The <a href="/facts/Ketal/DuwXfBMz">ketal</a> <a href="/facts/Protecting_group/f92hVwHl">protecting groups</a> of 9 are hydrolyzed to produce the diketone 10, which in turn is cyclized to form the cyclopentenone 11. The ketone of 11 is reacted with methyl lithium to yield the tertiary alcohol 12, which in turn is treated with acid to produce the tertiary cation 13. The key step of the synthesis is the π-cation cyclization of 13 in which the B-, C-, and D-rings of the steroid are simultaneously formed to produce 14. This step resembles the cationic cyclization reaction used in the biosynthesis of steroids and hence is referred to as biomimetic. In the next step the <a href="/facts/Enol/aySJNbQx">enol</a> <a href="/facts/Orthoester/CAcYfE2V">orthoester</a> is hydrolyzed to produce the ketone 15. The cyclopentene A-ring is then opened by oxidizing with ozone to produce 16. Finally, the diketone 17 undergoes an intramolecular <a href="/facts/Aldol_condensation/SydoYgEA">aldol condensation</a> by treating with aqueous potassium hydroxide to produce progesterone.<a class="footnote-ref" id="fnref:233" href="#fn:233">233</a>

<h2 id="history">History</h2>
<a href="/facts/George_W._Corner/1RcJUEYm">George W. Corner</a> and <a href="/facts/Willard_Myron_Allen/ac2LSMJv">Willard M. Allen</a> discovered the hormonal action of progesterone in 1929.<a class="footnote-ref" id="fnref:234" href="#fn:234">234</a><a class="footnote-ref" id="fnref:235" href="#fn:235">235</a><a class="footnote-ref" id="fnref:236" href="#fn:236">236</a><a class="footnote-ref" id="fnref:237" href="#fn:237">237</a> By 1931–1932, nearly pure crystalline material of high progestational activity had been isolated from the <a href="/facts/Corpus_luteum/rA91PnaC">corpus luteum</a> of animals, and by 1934, pure crystalline progesterone had been refined and obtained and the <a href="/facts/Chemical_structure/r5rT1Lj4">chemical structure</a> of progesterone was determined.<a class="footnote-ref" id="fnref:238" href="#fn:238">238</a><a class="footnote-ref" id="fnref:239" href="#fn:239">239</a> This was achieved by <a href="/facts/Adolf_Butenandt/Vzo8lDdT">Adolf Butenandt</a> at the <a href="/facts/Faculty_of_Chemistry%2c_Gda%25C5%2584sk_University_of_Technology/aFdYBAeI">Chemisches Institut</a> of <a href="/facts/Gda%25C5%2584sk_University_of_Technology/aFdYBAeI">Technical University</a> in <a href="/facts/Danzig/a6VNPK28">Danzig</a>, who extracted this new compound from several thousand liters of <a href="/facts/Urine/oNUYVtvX">urine</a>.<a class="footnote-ref" id="fnref:240" href="#fn:240">240</a>
<a href="/facts/Chemical_synthesis/3KXsVVwC">Chemical synthesis</a> of progesterone from <a href="/facts/Stigmasterol/At001R9e">stigmasterol</a> and <a href="/facts/Pregnanediol/mfWFYxxM">pregnanediol</a> was accomplished later that year.<a class="footnote-ref" id="fnref:241" href="#fn:241">241</a><a class="footnote-ref" id="fnref:242" href="#fn:242">242</a> Up to this point, progesterone, known generically as corpus luteum hormone, had been being referred to by several groups by different names, including corporin, lutein, luteosterone, and progestin.<a class="footnote-ref" id="fnref:243" href="#fn:243">243</a><a class="footnote-ref" id="fnref:244" href="#fn:244">244</a> In 1935, at the time of the Second International Conference on the Standardization of Sex Hormones in <a href="/facts/London%2c_England/KozCCsy9">London, England</a>, a compromise was made between the groups and the name progesterone (progestational steroidal ketone) was created.<a class="footnote-ref" id="fnref:245" href="#fn:245">245</a><a class="footnote-ref" id="fnref:246" href="#fn:246">246</a>

<h3>Veterinary use</h3>
The use of progesterone tests in dog breeding to pinpoint ovulation is becoming more widely used. There are several tests available but the most reliable test is a blood test with blood drawn by a veterinarian and sent to a lab for processing. Results can usually be obtained with 24 to 72 hours. The rationale for using progesterone tests is that increased numbers begin in close proximity to preovulatory surge in gonadotrophins and continue through ovulation and estrus. When progesterone levels reach certain levels they can signal the stage of estrus the female is. Prediction of birth date of the pending litter can be very accurate if ovulation date is known. Puppies deliver with a day or two of 9 weeks gestation in most cases. It is not possible to determine pregnancy using progesterone tests once a breeding has taken place, however. This is due to the fact that, in dogs, progesterone levels remain elevated throughout the estrus period.<a class="footnote-ref" id="fnref:247" href="#fn:247">247</a>

<h3>Pricing</h3>
Pricing for progesterone can vary depending location, insurance coverage, discount coupons, quantity, shortages, manufacturers, brand or generic versions, different pharmacies, and so on. As of currently, 30 capsules of 100 mg of the generic version, Progesterone, from CVS Pharmacy is around $40 without any discounts or insurance applied. The brand version, Prometrium, is around $450 for 30 capsules without any discounts or insurance applied.<a class="footnote-ref" id="fnref:248" href="#fn:248">248</a> In comparison, Walgreens offers 30 capsules of 100 mg in the generic version for $51 without insurance or coupons applied. The brand name costs around $431 for 30 capsules of 100 mg.<a class="footnote-ref" id="fnref:249" href="#fn:249">249</a>

<ul><li> This article incorporates <a href="https://en.wikiversity.org/wiki?curid=269289">text</a> available under the CC BY-SA 3.0 license.</li></ul>

<h2 id="external-links">External links</h2>
<ul><li><a href="http://gmd.mpimp-golm.mpg.de/Spectrums/5e8993d3-17a1-4a05-96f5-03ba3c2270af.aspx">Progesterone MS Spectrum</a></li>
<li><a href="https://meshb.nlm.nih.gov/record/ui?name=Progesterone">Progesterone</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li>
<li>Kimball JW (27 May 2007). <a href="https://web.archive.org/web/20080618062909/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Progesterone.html">"Progesterone"</a>. Kimball's Biology Pages. Archived from <a href="http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Progesterone.html">the original</a> on 18 June 2008. Retrieved 18 June 2008.</li></ul>

<h2 id="references">References</h2>

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<li id="fn:180">Csapo AI, Pulkkinen MO, Wiest WG (March 1973). "Effects of luteectomy and progesterone replacement therapy in early pregnant patients". American Journal of Obstetrics and Gynecology. 115 (6): 759–765. doi:10.1016/0002-9378(73)90517-6. PMID 4688578. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:180" class="footnote-back-ref">↩</a></li>
<li id="fn:181">NIH Clinical Center (16 August 2004). "Progesterone Historical Reference Ranges". United States National Institutes of Health. Archived from the original on 9 January 2009. Retrieved 12 March 2008. <a href="https://web.archive.org/web/20090109072721/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/Index/CB26894E1EB28DEF85256BA5005B000E?OpenDocument" target="_blank">https://web.archive.org/web/20090109072721/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/Index/CB26894E1EB28DEF85256BA5005B000E?OpenDocument</a> <a href="#fnref:181" class="footnote-back-ref">↩</a></li>
<li id="fn:182">Aufrère MB, Benson H (June 1976). "Progesterone: an overview and recent advances". Journal of Pharmaceutical Sciences. 65 (6): 783–800. doi:10.1002/jps.2600650602. PMID 945344. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:182" class="footnote-back-ref">↩</a></li>
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<li id="fn:190">Little, A. B., & Billiar, R. B. (1983). Progestagens. In Endocrinology of Pregnancy, 3rd Edition (pp. 92–111). Harper and Row Philadelphia. https://scholar.google.com/scholar?cluster=2512291948467467634 Archived 22 February 2022 at the Wayback Machine <a href="https://scholar.google.com/scholar?cluster=2512291948467467634" target="_blank">https://scholar.google.com/scholar?cluster=2512291948467467634</a> <a href="#fnref:190" class="footnote-back-ref">↩</a></li>
<li id="fn:191">Progesterone Reference Ranges, Performed at the Clinical Center at the National Institutes of Health, Bethesda MD, 03Feb09 <a href="https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument" target="_blank">https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument</a> <a href="#fnref:191" class="footnote-back-ref">↩</a></li>
<li id="fn:192">Progesterone Reference Ranges, Performed at the Clinical Center at the National Institutes of Health, Bethesda MD, 03Feb09 <a href="https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument" target="_blank">https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument</a> <a href="#fnref:192" class="footnote-back-ref">↩</a></li>
<li id="fn:193">Converted from mass values using molar mass of 314.46 g/mol <a href="#fnref:193" class="footnote-back-ref">↩</a></li>
<li id="fn:194">Converted from mass values using molar mass of 314.46 g/mol <a href="#fnref:194" class="footnote-back-ref">↩</a></li>
<li id="fn:195">Progesterone Reference Ranges, Performed at the Clinical Center at the National Institutes of Health, Bethesda MD, 03Feb09 <a href="https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument" target="_blank">https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument</a> <a href="#fnref:195" class="footnote-back-ref">↩</a></li>
<li id="fn:196">Progesterone Reference Ranges, Performed at the Clinical Center at the National Institutes of Health, Bethesda MD, 03Feb09 <a href="https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument" target="_blank">https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument</a> <a href="#fnref:196" class="footnote-back-ref">↩</a></li>
<li id="fn:197">Converted from mass values using molar mass of 314.46 g/mol <a href="#fnref:197" class="footnote-back-ref">↩</a></li>
<li id="fn:198">Converted from mass values using molar mass of 314.46 g/mol <a href="#fnref:198" class="footnote-back-ref">↩</a></li>
<li id="fn:199">Progesterone Reference Ranges, Performed at the Clinical Center at the National Institutes of Health, Bethesda MD, 03Feb09 <a href="https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument" target="_blank">https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument</a> <a href="#fnref:199" class="footnote-back-ref">↩</a></li>
<li id="fn:200">Progesterone Reference Ranges, Performed at the Clinical Center at the National Institutes of Health, Bethesda MD, 03Feb09 <a href="https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument" target="_blank">https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument</a> <a href="#fnref:200" class="footnote-back-ref">↩</a></li>
<li id="fn:201">Converted from mass values using molar mass of 314.46 g/mol <a href="#fnref:201" class="footnote-back-ref">↩</a></li>
<li id="fn:202">Converted from mass values using molar mass of 314.46 g/mol <a href="#fnref:202" class="footnote-back-ref">↩</a></li>
<li id="fn:203">Progesterone Reference Ranges, Performed at the Clinical Center at the National Institutes of Health, Bethesda MD, 03Feb09 <a href="https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument" target="_blank">https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument</a> <a href="#fnref:203" class="footnote-back-ref">↩</a></li>
<li id="fn:204">Progesterone Reference Ranges, Performed at the Clinical Center at the National Institutes of Health, Bethesda MD, 03Feb09 <a href="https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument" target="_blank">https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument</a> <a href="#fnref:204" class="footnote-back-ref">↩</a></li>
<li id="fn:205">Progesterone Reference Ranges, Performed at the Clinical Center at the National Institutes of Health, Bethesda MD, 03Feb09 <a href="https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument" target="_blank">https://web.archive.org/web/20150701024923/http://cclnprod.cc.nih.gov/dlm/testguide.nsf/0/CB26894E1EB28DEF85256BA5005B000E?OpenDocument</a> <a href="#fnref:205" class="footnote-back-ref">↩</a></li>
<li id="fn:206">Converted from mass values using molar mass of 314.46 g/mol <a href="#fnref:206" class="footnote-back-ref">↩</a></li>
<li id="fn:207">Converted from mass values using molar mass of 314.46 g/mol <a href="#fnref:207" class="footnote-back-ref">↩</a></li>
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</ol>

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