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Antiprogestins and Selective Progesterone Modulators

Antiprogestins are competitive inhibitors of progestins Progestins Compounds that interact with progesterone receptors in target tissues to bring about the effects similar to those of progesterone. Primary actions of progestins, including natural and synthetic steroids, are on the uterus and the mammary gland in preparation for and in maintenance of pregnancy. Hormonal Contraceptives at the progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors. Mifepristone is the only antiprogestin currently used in the United States. The most common clinical use of mifepristone is for the termination of pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care. Mifepristone is often combined with a prostaglandin such as misoprostol Misoprostol A synthetic analog of natural prostaglandin e1. It produces a dose-related inhibition of gastric acid and pepsin secretion, and enhances mucosal resistance to injury. It is an effective anti-ulcer agent and also has oxytocic properties. Eicosanoids. Selective progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors modulators (SPRMs) are closely related drugs with a slightly different mechanism of action, and act as either agonists or antagonists depending on the cellular environment. Ulipristal is the only SPRM used clinically in the US. It is used as an emergency contraceptive, and works by inhibiting luteinizing hormone and delaying ovulation Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle. The common side effects of antiprogestins and SPRMs include nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, and abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways.

Last updated: 29 Apr, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

  • Antiprogestins are competitive inhibitors of progestins Progestins Compounds that interact with progesterone receptors in target tissues to bring about the effects similar to those of progesterone. Primary actions of progestins, including natural and synthetic steroids, are on the uterus and the mammary gland in preparation for and in maintenance of pregnancy. Hormonal Contraceptives at the progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors ( PRs PRS Pierre robin sequence, also known as pierre robin syndrome or simply robin sequence, is a condition in infants that is characterized by a smaller-than-normal mandible, a tongue that retracts back into the throat, and difficulty breathing. Pierre Robin Sequence).
  • Selective progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors modulators (SPRMs) can act as either agonists or antagonists depending on the tissue type/cellular environment.

Classification

  • Antiprogestins: mifepristone
  • Selective progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors modulators (SPRMs): ulipristal

General indications

  • Pregnancy termination: mifepristone
  • Emergency contraception Emergency contraception Means of postcoital intervention to avoid pregnancy, such as the administration of postcoital contraceptives to prevent fertilization of an egg or implantation of a fertilized egg. Hormonal Contraceptives: ulipristal

Common side effects

  • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
  • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
  • Abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
  • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema

Physiology of progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones

  • Progesterone is secreted from the corpus luteum Corpus Luteum The yellow body derived from the ruptured ovarian follicle after ovulation. The process of corpus luteum formation, luteinization, is regulated by luteinizing hormone. Ovaries: Anatomy, placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity, testes Testes Gonadal Hormones, and adrenal cortex Adrenal Cortex The outer layer of the adrenal gland. It is derived from mesoderm and comprised of three zones (outer zona glomerulosa, middle zona fasciculata, and inner zona reticularis) with each producing various steroids preferentially, such as aldosterone; hydrocortisone; dehydroepiandrosterone; and androstenedione. Adrenal cortex function is regulated by pituitary adrenocorticotropin. Adrenal Glands: Anatomy.
  • Functions:
    • Development of the secretory endometrium Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development
    • Repression Repression Defense mechanisms involving approach and avoidance responses to threatening stimuli. The sensitizing process involves intellectualization in approaching or controlling the stimulus whereas repression involves unconscious denial in avoiding the stimulus. Defense Mechanisms of estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors expression
    • Thickening of the cervical mucus
    • Proliferation of acini in the mammary glands
    • Increase in body temperature Body Temperature The measure of the level of heat of a human or animal. Heatstroke
    • Maintenance of pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
    • Suppression Suppression Defense Mechanisms of uterine contractility
    • Decreases the frequency of gonadotropin-releasing hormone Gonadotropin-releasing hormone A decapeptide that stimulates the synthesis and secretion of both pituitary gonadotropins, luteinizing hormone and follicle stimulating hormone. Gnrh is produced by neurons in the septum preoptic area of the hypothalamus and released into the pituitary portal blood, leading to stimulation of gonadotrophs in the anterior pituitary gland. Puberty (GnRH) pulses
    • Increases insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing, leading to elevation of basal insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin levels
  • Mechanism of action:
    • Progesterone receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors ( PRs PRS Pierre robin sequence, also known as pierre robin syndrome or simply robin sequence, is a condition in infants that is characterized by a smaller-than-normal mandible, a tongue that retracts back into the throat, and difficulty breathing. Pierre Robin Sequence) are located in the cell cytoplasm.
    • PRs PRS Pierre robin sequence, also known as pierre robin syndrome or simply robin sequence, is a condition in infants that is characterized by a smaller-than-normal mandible, a tongue that retracts back into the throat, and difficulty breathing. Pierre Robin Sequence exist primarily as 1 of 2 isoforms: PR-A and PR-B
    • Binding of progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones → dimerization of the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → translocation to the nucleus Nucleus Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (cell nucleolus). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the endoplasmic reticulum. A cell may contain more than one nucleus. The Cell: Organelles → binding to progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones response elements (PREs) on target genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure → regulation of gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription

Antiprogestins: Mifepristone

Chemical structure

Mifepristone is a synthetic steroid hormone.

Chemical structure of mifepristone

Chemical structure of mifepristone:
A frequently prescribed antiprogestin, mifepristone is a derivative of 19-norprogestin.

Image: “Mifepristone structure” by Vaccinationist. License: Public Domain

Mechanism of action

  • Antagonist and partial agonist of PR-A and PR-B
  • In the absence of progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones, antiprogestins act as partial agonists.
  • At high doses, mifepristone acts as a glucocorticoid receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors antagonist (therefore, it is useful in treating Cushing’s syndrome).

Pharmacological effects

Antiprogestin actions:

  • Pharmacological effects depend on the timing of drug administration.
  • Mifepristone can delay ovulation Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle when given during the follicular phase Follicular phase The period of the menstrual cycle representing follicular growth, increase in ovarian estrogen (estrogens) production, and epithelial proliferation of the endometrium. Follicular phase begins with the onset of menstruation and ends with ovulation. Menstrual Cycle.
  • When administered during the luteal phase Luteal phase The period in the menstrual cycle that follows ovulation, characterized by the development of corpus luteum, increase in progesterone production by the ovary and secretion by the glandular epithelium of the endometrium. The luteal phase begins with ovulation and ends with the onset of menstruation. Menstrual Cycle:
    • Induction of menstruation Menstruation The periodic shedding of the endometrium and associated menstrual bleeding in the menstrual cycle of humans and primates. Menstruation is due to the decline in circulating progesterone, and occurs at the late luteal phase when luteolysis of the corpus luteum takes place. Menstrual Cycle
    • Prevention of secretory changes in the endometrium Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development
  • When given during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care → induces expulsion of products of conception via the following process:
    • Inhibition of decidualization →
    • Detachment of the blastocyst Blastocyst A post-morula preimplantation mammalian embryo that develops from a 32-cell stage into a fluid-filled hollow ball of over a hundred cells. A blastocyst has two distinctive tissues. The outer layer of trophoblasts gives rise to extra-embryonic tissues. The inner cell mass gives rise to the embryonic disc and eventual embryo proper. Fertilization and First Week
    • Hormonal changes:
      • ↓ in hCG secretion Secretion Coagulation Studies
      • ↓ in the secretion Secretion Coagulation Studies of progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones from the corpus luteum Corpus Luteum The yellow body derived from the ruptured ovarian follicle after ovulation. The process of corpus luteum formation, luteinization, is regulated by luteinizing hormone. Ovaries: Anatomy
      • ↑ in prostaglandin secretion Secretion Coagulation Studies
    • Cervical softening and ↑ myometrial contractions →
    • Expulsion of products of conception
  • When used for pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care termination, bleeding is expected to last on average 9‒16 days (though may be up to 30 days in some cases)

Antiglucocorticoid effect:

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

The following information is for the representative antiprogestin, mifepristone:

  • Orally active
  • Bioavailability Bioavailability Pharmacokinetics and Pharmacodynamics: 70%
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 18 hours
  • Time to peak: 90 minutes
  • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy by cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury (CYP)3A4 
  • Undergoes enterohepatic circulation Enterohepatic Circulation Recycling through liver by excretion in bile, reabsorption from intestines (intestinal reabsorption) into portal circulation, passage back into liver, and re-excretion in bile. Pharmacokinetics and Pharmacodynamics
  • Excreted in feces

Indications

  • Termination of pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care: often used in combination with misoprostol Misoprostol A synthetic analog of natural prostaglandin e1. It produces a dose-related inhibition of gastric acid and pepsin secretion, and enhances mucosal resistance to injury. It is an effective anti-ulcer agent and also has oxytocic properties. Eicosanoids
  • Can be used as a component of treatment for early pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care loss
  • Emergency contraception Emergency contraception Means of postcoital intervention to avoid pregnancy, such as the administration of postcoital contraceptives to prevent fertilization of an egg or implantation of a fertilized egg. Hormonal Contraceptives (the low dose required for this indication is not available in the US, though it is used in several other countries)
  • Cushing’s syndrome: for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship who have failed surgery or are not suitable candidates for surgery

Side effects

  • GI:
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting
    • Abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea or constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
    • GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease (GERD)
  • Nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification:
  • Endocrine:
    • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
    • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
    • Adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison’s Disease
  • Gynecologic: vaginal bleeding/hemorrhage
  • Cardiovascular: hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Systemic: anaphylactic reactions Anaphylactic reactions An acute hypersensitivity reaction due to exposure to a previously encountered antigen. The reaction may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock, and death. Vaccination
  • Dermatologic: toxic epidermal necrolysis Toxic Epidermal Necrolysis Stevens-Johnson Syndrome

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • Desired pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
  • Hypersensitivity to drug or its components
  • Patients taking simvastatin Simvastatin A derivative of lovastatin and potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic ldl receptors, it increases breakdown of ldl cholesterol. Statins, lovastatin Lovastatin A fungal metabolite isolated from cultures of aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. Statins, and CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) substrates
  • Unexplained vaginal bleeding
  • Endometrial atypia Atypia Fibrocystic Change or endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer

Cautions

  • Patients presenting with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, generalized malaise Malaise Tick-borne Encephalitis Virus, or diarrhea > 24 hours after taking mifepristone should be evaluated for infection.
  • Possibility of Clostridium sordellii infection
  • Patients should be counseled to seek medical attention Attention Focusing on certain aspects of current experience to the exclusion of others. It is the act of heeding or taking notice or concentrating. Psychiatric Assessment in case of heavy vaginal bleeding.

Selective Progesterone Receptor Modulators: Ulipristal

Chemical structure

Chemical structure of ulipristal

Chemical structure of ulipristal, a selective progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors modulator:
A derivative of 19-norprogesterone

Image: “Ulipristal acetate skeletal” by Anypodetos. License: Public Domain

Mechanism of action

  • PR antagonists and partial agonists
  • Function depends on the concentration of coactivators and corepressors:
    • In cells with excess coactivators: SPRMs act as agonists
    • In cells with excess corepressors: SPRMs act as antagonists

Pharmacological effects

  • Suppression Suppression Defense Mechanisms of luteinizing hormone ( LH LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle) surge 
  • Delay or inhibition of ovulation Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle
  • Reduction in endometrial thickness
  • May inhibit implantation Implantation Endometrial implantation of embryo, mammalian at the blastocyst stage. Fertilization and First Week

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

The following information is for the stereotypical SPRM, ulipristal:

  • Oral absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: rapid
  • Protein binding: > 94%
  • Time to peak: 1 hour
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 32–38 hours
  • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy by CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) to monomethylated ulipristal acetate, the active metabolite

Indications

Ulipristal is indicated for emergency contraception.

Side effects

  • Nervous System:
  • GI:
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting
    • Abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Gynecologic:
    • Dysmenorrhea
    • Irregular menstruation Menstruation The periodic shedding of the endometrium and associated menstrual bleeding in the menstrual cycle of humans and primates. Menstruation is due to the decline in circulating progesterone, and occurs at the late luteal phase when luteolysis of the corpus luteum takes place. Menstrual Cycle
  • Systemic: fatigue

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation and cautions

  • Contraindication: pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
  • Cautions:
    • Use with caution in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship taking CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) inducers and inhibitors.
    • Bleeding irregularities are possible (delay in menstruation Menstruation The periodic shedding of the endometrium and associated menstrual bleeding in the menstrual cycle of humans and primates. Menstruation is due to the decline in circulating progesterone, and occurs at the late luteal phase when luteolysis of the corpus luteum takes place. Menstrual Cycle, intermenstrual bleeding).

Comparison of Antiprogestins and SPRMs

Table: Comparison of antiprogestins and selective progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors modulators
Category Antiprogestins SPRMs
Mechanism of action Antagonists of progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors A and B
  • In cells with excess coactivators: SPRMs act as agonists
  • In cells with excess corepressors: SPRMs act as antagonists
Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics 18 hours 32–38 hours
Time to peak 90 minutes 1 hour
Primary indications Emergency contraception Emergency contraception Means of postcoital intervention to avoid pregnancy, such as the administration of postcoital contraceptives to prevent fertilization of an egg or implantation of a fertilized egg. Hormonal Contraceptives
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation
  • Hypersensitivity to drug or components
  • Pregnancy
  • Patients taking simvastatin Simvastatin A derivative of lovastatin and potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic ldl receptors, it increases breakdown of ldl cholesterol. Statins, lovastatin Lovastatin A fungal metabolite isolated from cultures of aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme a reductase, which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. Statins, and CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) substrates
  • Unexplained vaginal bleeding
  • Endometrial atypia Atypia Fibrocystic Change or endometrial cancer Endometrial Cancer Endometrial carcinoma (EC) is the most common gynecologic malignancy in the developed world, and it has several histologic types. Endometrioid carcinoma (known as type 1 EC) typically develops from atypical endometrial hyperplasia, is hormonally responsive, and carries a favorable prognosis. Endometrial Hyperplasia and Endometrial Cancer
Pregnancy
SPRM: selective progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors modulator
CYP: cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury

References

  1. Tripathi, K.D. (2018). Chapter 22: Estrogens, progestins and contraceptives. In Tripathi, M. (Ed.), Essentials of Medical Pharmacology. JP Medical Ltd. pp. 341–346.
  2. Chrousos, G.P. (2017). The gonadal hormones & inhibitors. In Katzung, B. G., et al. (Eds.), Basic & Clinical Pharmacology. New York: McGraw-Hill Medical. p.738.
  3. Levin, E.R., Vitek, W.S., Hammes, S.R. (2017). Estrogens, progestins, and the female reproductive tract. In Brunton, L.L., et al. (Eds.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York:McGraw-Hill Medical, pp. 815–816.
  4. Autry, B.M., Wadhwa, R. (2021). Mifepristone. StatPearls. Retrieved June 17, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK557612/
  5. Jadav, S.P., Parmar, D.M. (2012). Ulipristal acetate, a progesterone receptor modulator for emergency contraception. Journal of Pharmacology & Pharmacotherapeutics. 3(2), 109–111. https://pubmed.ncbi.nlm.nih.gov/22629083/
  6. Lexicomp. (2022). Mifepristone: Drug information. In UpToDate. Retrieved Feb 23, 2022 from https://www.uptodate.com/contents/mifepristone-drug-information
  7. Lexicomp. (2022). Ulipristal: Drug information. In UpToDate. Retrieved Feb 23, 2022 from https://www.uptodate.com/contents/ulipristal-drug-information
  8. Bartz, D.A., and Blumenthal, P.D. (2021). First-trimester pregnancy termination: Medication abortion. In UpToDate. Retrieved Feb 23, 2022 from https://www.uptodate.com/contents/first-trimester-pregnancy-termination-medication-abortion

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