Editing Combined oral contraceptive pill (section)

==Mechanism of action==
Progesterone and Oestrogen, either in combination or with Progesterone-only, are the [[Active ingredient|active pharmaceutical ingredients]] found in a hormonal oral contraceptive formulation.<ref name=":2a">{{Cite web |title=Estrogen and Progestin (Oral Contraceptives): MedlinePlus Drug Information |url=https://medlineplus.gov/druginfo/meds/a601050.html |access-date=2024-02-28 |website=medlineplus.gov }}</ref> These medications are [[Orally ingested|orally]] administered for [[systemic absorption]] to exert their effects.<ref name=":2a" /> An artificially enhanced level of Progesterone throughout the menstrual cycle inhibits the pituitary secretion of FSH and LH such that their actions in stimulating follicular development and ovulation are prevented.<ref name=":0a" /> Similarly, a boosted Oestrogen level activates the negative feedback mechanism in reducing FSH secretion from pituitary and therefore prevents follicular development.<ref name=":0a" /> In the absence of a developed follicle, ovulation cannot occur so that [[fertilisation]] is made impossible and [[contraception]] is achieved.<ref name=":2a" /> In comparison, Progesterone is more efficacious than Oestrogen not only because of its additional action in impeding LH, but also its ability to modulate the cervical mucus into sperm-repellent.<ref name=":0a" />

Combined oral contraceptive pills were developed to prevent [[ovulation]] by suppressing the release of [[gonadotropin]]s. Combined hormonal contraceptives, including combined oral contraceptive pills, inhibit [[follicular phase|follicular development]] and prevent ovulation as a primary mechanism of action.<ref name="Nelson 2011">{{cite book| veditors = Hatcher RA, Trussell J, Nelson A, Cates W, Kowal D, Policar M | title = Contraceptive technology| edition = 20th revised| year = 2011| publisher = Ardent Media| location = New York| isbn = 978-1-59708-004-0| oclc = 781956734| pages = 249–341| chapter = Combined oral contraceptives (COCs)| issn = 0091-9721 }} pp. 257–258:{{blockquote|Mechanism of action<br /> Combined oral contraceptive pills prevent fertilization and, therefore, qualify as contraceptives. There is no significant evidence that they work after fertilization. The progestins in all combined oral contraceptives provide most of the contraceptive effect by suppressing ovulation and thickening cervical mucus, although the estrogens also make a small contribution to ovulation suppression. Cycle control is enhanced by the estrogen.<br />Because combined oral contraceptives so effectively suppress ovulation and block ascent of sperm into the upper genital tract, the potential impact on endometrial receptivity to implantation is almost academic. When the two primary mechanisms fail, the fact that pregnancy occurs despite the endometrial changes demonstrates that those endometrial changes do not significantly contribute to the pill's mechanism of action.}}</ref><ref name="Speroff 2011">{{cite book| vauthors = Speroff L, Darney PD | title = A clinical guide for contraception| edition = 5th| year = 2011| publisher = Lippincott Williams & Wilkins| location = Philadelphia| isbn = 978-1-60831-610-6| pages = 19–152| chapter = Oral contraception }}</ref><ref name="Levin 2011">{{cite book| vauthors = Levin ER, Hammes SR | veditors = Goodman LS, Brunton LL, Chabner BA, Knollmann BC | title = Goodman & Gilman's pharmacological basis of therapeutics| edition = 12th| year = 2011| publisher = McGraw-Hill Medical| location = New York| isbn = 978-0-07-162442-8| pages = 1163–1194| chapter = Estrogens and progestins }}</ref><ref name="Glasier 2010">{{cite book| vauthors = Glasier A | author-link = Anna Glasier| veditors = Jameson JL, De Groot LJ | title = Endocrinology| edition = 6th| year = 2010| publisher = Saunders Elsevier| location = Philadelphia| isbn = 978-1-4160-5583-9| pages = 2417–2427| chapter = Contraception }}</ref>

Under normal circumstances, [[luteinizing hormone]] (LH) stimulates the [[Theca of follicle|theca cells]] of the ovarian follicle to produce [[androstenedione]]. The [[granulosa cell]]s of the ovarian follicle then convert this androstenedione to estradiol. This conversion process is catalyzed by aromatase, an enzyme produced as a result of [[follicle-stimulating hormone]] (FSH) stimulation.<ref>{{Citation |last=Barbieri |first=Robert L. |title=The Endocrinology of the Menstrual Cycle |date=2014 |url=https://doi.org/10.1007/978-1-4939-0659-8_7 |work=Human Fertility: Methods and Protocols |series=Methods in Molecular Biology |volume=1154 |pages=145–169 |editor-last=Rosenwaks |editor-first=Zev |place=New York, NY |publisher=Springer |doi=10.1007/978-1-4939-0659-8_7 |pmid=24782009 |isbn=978-1-4939-0659-8 |access-date=15 September 2022 |editor2-last=Wassarman |editor2-first=Paul M. |archive-date=15 July 2023 |archive-url=https://web.archive.org/web/20230715025752/https://link.springer.com/protocol/10.1007/978-1-4939-0659-8_7 |url-status=live }}</ref> In individuals using oral contraceptives, progestogen [[negative feedback]] decreases the pulse frequency of [[gonadotropin-releasing hormone]] (GnRH) release by the [[hypothalamus]], which decreases the secretion of FSH and greatly decreases the secretion of LH by the [[anterior pituitary]]. Decreased levels of FSH inhibit follicular development, preventing an increase in [[estradiol]] levels. Progestogen negative feedback and the lack of estrogen [[positive feedback]] on LH secretion prevent a [[menstrual cycle|mid-cycle]] LH surge. Inhibition of follicular development and the absence of an LH surge prevent ovulation.<ref name="Nelson 2011"/><ref name="Speroff 2011"/><ref name="Levin 2011"/>

Estrogen was originally included in oral contraceptives for better cycle control (to stabilize the endometrium and thereby reduce the incidence of breakthrough bleeding), but was also found to inhibit follicular development and help prevent ovulation. Estrogen negative feedback on the anterior pituitary greatly decreases the secretion of FSH, which inhibits follicular development and helps prevent ovulation.<ref name="Nelson 2011"/><ref name="Speroff 2011"/><ref name="Levin 2011"/>

Another primary mechanism of action of all progestogen-containing contraceptives is inhibition of [[spermatozoon|sperm]] penetration through the [[cervix]] into the upper [[female reproductive system (human)|genital tract]] ([[uterus]] and [[fallopian tube]]s) by decreasing the water content and increasing the [[viscosity]] of the [[cervical mucus]].<ref name="Nelson 2011"/>

The estrogen and progestogen in combined oral contraceptive pills have other effects on the reproductive system, but these have not been shown to contribute to their contraceptive efficacy:<ref name="Nelson 2011"/>
* Slowing tubal motility and ova transport, which may interfere with [[human fertilization|fertilization]].
* [[Endometrium|Endometrial]] atrophy and alteration of [[metalloproteinase]] content, which may impede sperm motility and viability, or theoretically inhibit [[implantation (human embryo)|implantation]].
* Endometrial edema, which may affect implantation.

Insufficient evidence exists on whether changes in the endometrium could actually prevent implantation. The primary mechanisms of action are so effective that the possibility of fertilization during combined oral contraceptive pill use is very small. Since pregnancy occurs despite endometrial changes when the primary mechanisms of action fail, endometrial changes are unlikely to play a significant role, if any, in the observed effectiveness of combined oral contraceptive pills.<ref name="Nelson 2011"/>