progesterone
Regulatory sources consulted
Approved indications
- Luteal-phase support as part of an assisted reproductive technology program.
Contraindications
Absolute
- Undiagnosed vaginal bleeding, progesterone-sensitive neoplasia, porphyria, missed abortion, or ectopic pregnancy.
- Current or prior arterial or venous thromboembolism, severe thrombophlebitis, severe liver disease, or hypersensitivity.
Clinical warnings
- Major warning · Stop for myocardial infarction, stroke, venous thrombosis, pulmonary embolism, thrombophlebitis, or retinal thrombosis. Monitor depression, fluid retention, diabetes, and liver function. — CIMA/AEMPS, ficha técnica 82250
Drug interactions
- ModerateCYP3A4 inducers
Mechanism: Rifampin, carbamazepine, and phenytoin may reduce progesterone bioavailability.
Recommendation: Review effectiveness and treatment with the assisted-reproduction team.
CIMA/AEMPS, ficha técnica 82250https://cima.aemps.es/cima/dochtml/ft/82250/FT_82250.html
- ModerateOther vaginal products
Mechanism: Vaginal coadministration has not been evaluated and may alter local exposure.
Recommendation: Simultaneous use is not recommended.
CIMA/AEMPS, ficha técnica 82250https://cima.aemps.es/cima/dochtml/ft/82250/FT_82250.html
Adverse events
Common (≥1%)
Somnolence · Mood changes · Abdominal distension or pain · Constipation · Hot flushes · Breast pain · Fatigue
Rare but serious
Arterial, venous, or retinal thrombosis · Severe hypersensitivity reaction
Pregnancy and lactation
It is indicated only during the first trimester as assisted-reproduction support. Data on congenital anomalies, including male and female genital abnormalities after intrauterine exposure, are limited and incomplete; trial exposure was too low to draw conclusions. It should not be used while breastfeeding because progesterone is detectable in milk.
Recent literature (PubMed)
The progesterone receptor (PR) modulates estrogen receptors α (ERα) action in breast cancer; it is an upregulated target gene of ER, and its expression is dependent on estrogen. PR is also a valuable prognostic biomarker in breast cancer, especially in hormone-positive breast cancer. High expression of PR is more frequently observed in tumors with a better baseline prognosis (ie, luminal A) than tumors with a poor baseline prognosis (ie, luminal B). In the following review, we present the role of PR in breast cancer, including the genomic characteristics and pathways in breast cancer, PR and endocrine therapy.
Estrogens have been associated with an increase in breast cancer risk. Yet emerging clinical and experimental evidence points to progestogens [endogenous progesterone or synthetic progesterone (progestin)] as the primary hormonal driver underlying seemingly estrogen-associated breast cancer risk. Estrogens may contribute to breast cancer risk indirectly by induction of the progesterone receptor and thus amplifying progesterone signaling. Large studies of hormonal contraceptives suggest that the small increase in breast cancer risk from hormonal contraceptives is mainly attributable to progestins, not estrogens. Estrogen-plus-progestin hormone replacement therapy (HRT) has consistently shown an increase in breast cancer risk among postmenopausal women, whereas estrogen-alone HRT has little impact on breast cancer risk in naturally or surgically menopausal women. In particular, the long-term follow-up of the Women's Health Initiative (WHI) randomized trials suggests a benefit of estrogen alone. Recent data further indicate that endogenously elevated estrogen during assisted reproductive technology (ART) exhibits little adverse effect on or potentially a reduction in breast cancer risk and recurrence. Also, accumulating evidence suggests that inhibition of progesterone signaling is a critical mechanism underlying the risk-reducing and therapeutic effects of antiestrogens. Estrogen HRT has shown an array of proven benefits, including ameliorating menopausal symptoms and improving bone health. Collective evidence thus suggests that estrogen HRT is likely to offer health benefits to perimenopausal or postmenopausal women, including breast cancer survivors, as well as young BRCA1/2 carriers with prophylactic oophorectomy for ovarian cancer prevention.
Endometriosis and adenomyosis are closely related disorders. Their pathophysiologies are extremely similar. Both tissues originate from the eutopically located intracavitary endometrium. Oligoclones of endometrial glandular epithelial cells with somatic mutations and attached stromal cells may give rise to endometriosis if they travel to peritoneal surfaces or the ovary via retrograde menstruation and/or may be entrapped in the myometrium to give rise to adenomyosis. In both instances, the endometrial cell populations possess survival and growth capabilities conferred by somatic epithelial mutations and epigenetic abnormalities in stromal cells. Activating mutations of KRAS are the most commonly found genetic variant in endometriotic epithelial cells, whereas the adenomyotic epithelial cells almost exclusively bear KRAS mutations. Epigenetic abnormalities in the stromal cells of endometriosis and adenomyosis are very similar and involve an abnormal expression pattern of nuclear receptors, including the steroid receptors. These epigenetic defects give rise to excessive local estrogen biosynthesis by aromatase and abnormal estrogen action via estrogen receptor-β. Deficient progesterone receptor expression results in progesterone resistance in both endometriosis and adenomyosis.
Uterine fibroids (leiomyomas), the most common tumors in women and those assigned female at birth, originate from myometrial smooth muscle cells and cause heavy menstrual bleeding, anemia, pelvic discomfort, pregnancy loss, and obstruction of labor in approximately a quarter of reproductive-age women. During each ovulatory cycle, the myometrium responds to the ovarian steroids, estradiol, and progesterone, via increased tissue stem cell proliferation to prepare for impending pregnancy, during which a somatic mutation may arise to initiate a tumor. Both the mutated smooth muscle cells and the adjacent tumor-associated fibroblasts lay down excessive quantities of extracellular matrix, providing a unique feature that led to naming these tumors "fibroids." The most common somatic mutations in fibroids affect the Mediator complex subunit 12 (MED12; 77%) and high-mobility group AT-hook 2/1 (HMGA2/1; 10%) genes. Heterozygous mutations in MED12, a chromatin-associated protein, disrupt the attached CDK8 kinase module in the Mediator complex. MED12 mutations are associated with increased genomic instability, altered chromatin landscape and enhancer engagement, and increased responsiveness to progesterone. Progesterone and a small stem cell population in a fibroid are essential for tumor survival and growth. Progesterone, via its receptors in differentiated fibroid cell populations, activates the production of Wingless-type MMTV integration site family (WNT) ligands, cytokines, and other growth substances to act on adjacent stem cells in a paracrine fashion to support tumor growth. Suppression of estrogen or progesterone production and progesterone antagonists have been used for temporary shrinkage of these tumors and symptom relief. Here we provide an overview of these mechanisms and future approaches for prevention and medical management of uterine fibroids. This fact sheet is about exposure to progesterone and progestins in pregnancy and while breastfeeding. This informatio