The thickness of the stratum functionalis is reestablished under the proliferative effects of estradiol-17β by the time ovulation occurs. Following ovulation, the corpus luteum produces high levels of progesterone along with estradiol-17β. This luteal phase of the ovary switches the uterine endometrium from the proliferative phase to the secretory phase. Generally, progesterone inhibits further growth of the endometrium and promotes differentiation of epithelial and stromal cells. Progesterone also stimulates the uterine glands to secrete a nutrient-rich substance that supports the viability of the blastocyst. As the secretory phase progresses, the uterine glands become corkscrewed and sacculated. Progesterone also induces changes in the adhesivity of the surface epithelium, creating a "window of receptivity" for implantation of an embryo. Additionally, progesterone encourages the differentiation of stromal cells into "predecidual cells," which are necessary for the formation of the decidua during pregnancy or for the orchestration of menstruation in the absence of pregnancy.

Progesterone opposes the proliferative effects of estradiol-17β and downregulates the estrogen receptor (ER). It also induces the formation of inactivating isoforms of 17β-HSD, converting active estradiol-17β into inactive estrone. This opposition of the mitogenic effects of estradiol-17β by progesterone is crucial for protecting the uterine endometrium against estrogen-induced uterine cancer. On the other hand, the administration of "unopposed estrogen" significantly increases the risk of uterine cancer in women.

Selective estrogen receptor modulators (SERMs) like tamoxifen, for example, are used as ER antagonists in the treatment of breast cancer, which is promoted by estrogen. When SERMs bind to the ER, they induce conformational changes that allow co-repressor proteins to bind to the ER or promote degradation of the ER, or both. Tamoxifen, however, has some uterotrophic activity, meaning it causes the growth of uterine endometrial tissue. Therefore, newer SERMs like raloxifene have been developed to have ER antagonist activity on the breast, beneficial ER agonist activity on bone, and either no activity or ER antagonist activity on the uterine endometrium.

In a nonfertile cycle, the death of the corpus luteum leads to a sudden withdrawal of progesterone, resulting in changes in the uterine endometrium and the shedding of the lamina functionalis. This shedding is known as menstruation or a period and typically lasts for 4 to 5 days, with blood loss ranging from 25 to 35 mL. Menstruation coincides with the early follicular phase of the ovary.

The myometrium is regulated hormonally.
By ovulation, the thickness of the stratum functionalis has been reestablished under the proliferative actions of estradiol-17β (see
Fig. 44.27 ). After ovulation the corpus luteum produces high levels of progesterone along with estradiol-17β. The luteal phase of the ovary switches the proliferative phase of the uterine endometrium to the secretory phase. In general, progesterone inhibits further endometrial growth and induces differentiation of epithelial and stromal cells. Progesterone induces the uterine glands to secrete a nutrient-rich product that supports blastocyst viability. As the secretory phase proceeds the mucosal uterine glands become corkscrewed and sacculated (see
Fig.
44.27 ). Progesterone also induces changes in adhesivity of the surface epithelium, thereby generating the “window of receptivity” for implantation of an embryo (see nancy). Additionally, progesterone promotes differentiation of stromal cells into “predecidual cells,” which must be prepared to form the decidua of pregnancy or to orchestrate menstruation in the absence of pregnancy.
•Fig. 44.28 Molecularmechanismbywhichtheestrogenreceptor(ER)regulatesgeneexpression.Left, Estradiol-17β bindstotheERandchangesitsconformationsothatitbindsasadimertoestrogen-responseelement(ERE)andrecruitscoactivatorproteins(Co-Act),whichleadstostimulationofgeneexpression.Right, Selectiveestrogenreceptormodulators(SERMs),suchastamoxifeninthebreast,alterERconformationsothatitrecruitsco-repressorproteins(Co-Rep),therebyinhibitinggeneexpression.InthiscasetheSERMactsasanERantagonist,butinsometissuesthesameSERMcanactasanERagonist.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.)
Progesteroneopposestheproliferativeactionsofestradiol-17β anddownregulatestheestrogenreceptor(ER).Progesteronealsoinducesinactivating isoforms of 17β-HSD, therebyconvertingtheactiveestradiol-17β intotheinactiveestrone.Thisoppositionofthemitogenicactionsofestradiol-17β byprogesteroneisimportanttoprotecttheuterineendometriumfromestrogen-induceduterinecancer.Incontrast,administrationof“unopposed estrogen” towomensignificantlyincreasestheriskforuterinecancer.
Fig.44.28 ).Forexample,theSERMtamoxifen isusedasanERantagonistforthetreatmentofbreastcancer(whoseearlyprogressionispromotedbyestrogen).BindingofSERMtotheERinducesconformationalchangesthatallowco-repressorstobindtotheERorpromotedegradationoftheER(orboth;see
Fig.
44.28 ).Becausetamoxifenhassomeuterotropicactivity(i.e.,makesuterineendometrialtissuegrow),newerSERMssuchasraloxifene havebeendevelopedtohaveERantagonistactivityonthebreast,beneficialERagonistactivityonbone(seelater),andnoactivityorERantagonisticactivityontheuterineendometrium.
In a nonfertile cycle, death of the corpus luteum results in sudden withdrawal of progesterone, which leads to changes in the uterine endometrium that result in loss of the lamina functionalis (see Fig. 43.27). Menstruation normally lasts for 4 to 5 days (called a period), and the volume of blood loss ranges from 25 to 35 mL. Menstruation coincides with the early follicular phase of the ovary.
Hormonal Regulation of the Myometrium