Antiprogestins and Selective Progesterone Modulators

Antiprogestins are competitive inhibitors of progestins at the progesterone receptors. Mifepristone, lilopristone, and onapristone are the 3 antiprogestins that are currently used. The most common clinical use of mifepristone is for the termination of pregnancy. Mifepristone is often combined with a prostaglandin such as misoprostol. Selective receptor progesterone 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. Examples of SPRMs include ulipristal, asoprisnil, and telapristone. Ulipristal is used as an emergency contraceptive; its mechanism of action is by the inhibition of luteinizing hormone and delaying ovulation. The common side effects of antiprogestins and SPRMs include nausea, vomiting, and abdominal pain.

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Overview

Definition

Antiprogestins are competitive inhibitors of progestins at the progesterone receptors (PRs).

Classification

  • Antiprogestins:
    • Mifepristone
    • Lilopristone
    • Onapristone
  • Selective progesterone receptor modulators (SPRMs):
    • Ulipristal
    • Asoprisnil
    • Telapristone

General indications

  • Contraception
  • Pregnancy termination
  • Uterine fibroids

Common side effects

  • Nausea
  • Vomiting
  • Abdominal pain

Physiology

  • Progesterone is secreted from the corpus luteum, placenta, testes, and adrenal cortex.
  • Functions:
    • Development of the secretory endometrium
    • Repression of estrogen receptor expression
    • Thickening of the cervical mucus
    • Proliferation of acini in the mammary glands
    • Increase in body temperature
    • Maintenance of pregnancy
    • Suppression of uterine contractility
    • Decreases the frequency of gonadotropin-releasing hormone (GnRH) pulses
    • Elevation of basal insulin levels
  • Mechanism of action:
    • PRs are located in the cell nucleus.
    • PRs consist of 2 isoforms: PR-A and PR-B
    • Binding of progesterone → dimerization of the receptor → binding to progesterone response elements (PREs) on target genes → regulation of gene transcription
    • Progesterone binds to cell membrane receptors:
      • Oocyte maturation
      • Increased Ca2+ release from spermatozoa

Antiprogestins

Chemical structure

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

Classification

The 3 drugs in the antiprogestin class include:

  • Mifepristone
  • Lilopristone
  • Onapristone

Mechanism of action

  • Antagonist and partial agonist of PR-A and PR-B
  • In the absence of progesterone, antiprogestins act as partial agonists.
  • At high doses, mifepristone acts as a glucocorticoid receptor 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 when given during the follicular phase.
    • When administered during the luteal phase:
      • Induction of menstruation
      • Prevention of secretory changes in the endometrium
    • When given during pregnancy → inhibition of decidualization → detachment of the blastocyst → decrease in hCG secretion → decrease in the secretion of progesterone from the corpus luteum → increase in prostaglandin secretion → cervical softening and ↑ myometrial contractions
  • Antiglucocorticoid effect: blocks the negative feedback inhibition by cortisol

Pharmacokinetics

The following information is for the representative antiprogestin, mifepristone:

  • Orally active
  • Bioavailability: 25%
  • Half-life: 18 hours
  • Time to peak: 90 minutes
  • Metabolized in the liver by cytochrome P450 (CYP)3A4 
  • Undergoes enterohepatic circulation
  • Excreted in feces

Indications

  • Termination of pregnancy: often used in combination with misoprostol
  • Cervical maturation
  • Emergency contraception
  • Induction of labor
  • Cushing’s syndrome: for patients who have failed surgery or are not suitable candidates for surgery
  • Endometriosis
  • Uterine fibroids
  • Breast cancer
  • Meningioma

Side effects

  • GI:
    • Nausea and vomiting
    • Abdominal pain
    • Diarrhea or constipation
    • GERD
  • Nervous system:
    • Headache
    • Dizziness
  • Infectious:
    • Sinusitis
    • Pharyngitis
    • Stomatitis
  • Endocrine:
    • Hypoglycemia
    • Adrenal insufficiency
  • Gynecologic: vaginal bleeding
  • Cardiovascular: hypertension
  • Systemic: anaphylactic reactions
  • Dermatologic: toxic epidermal necrolysis

Contraindications

  • Hypersensitivity to drug or its components
  • Control of hyperglycemia during pregnancy
  • Patients taking simvastatin, lovastatin, and CYP3A4 substrates
  • Vaginal bleeding
  • Endometrial atypia or endometrial cancer

Cautions

  • Patients presenting with fever, generalized malaise, 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 in case of heavy vaginal bleeding.

Selective Progesterone Receptor Modulators

Chemical structure

Chemical structure of ulipristal

Chemical structure of ulipristal, a selective progesterone receptor 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 of luteinizing hormone (LH) surge 
  • Delay or inhibition of ovulation
  • Inhibition of follicular rupture
  • Reduction in endometrial thickness
  • May inhibit implantation

Pharmacokinetics

The following information is for the stereotypical SPRM, ulipristal:

  • Protein binding: > 94%
  • Time to peak: 1 hour
  • Half-life: 32–38 hours
  • Metabolized in the liver by CYP3A4 to monomethylated ulipristal acetate, the active metabolite

Indications

  • Emergency contraception
  • Uterine fibroids
  • Endometriosis (novel, undergoing clinical trials)

Side effects

  • Nervous System:
    • Headache
    • Dizziness
  • GI:
    • Nausea and vomiting
    • Abdominal pain
  • Gynecologic:
    • Dysmenorrhea
    • Menstrual delay
  • Systemic: fatigue

Contraindications and cautions

  • Contraindication: pregnancy
  • Cautions:
    • Use with caution in patients taking CYP3A4 inducers and inhibitors.
    • Bleeding irregularities are possible (delay in menstruation, intermenstrual bleeding).

Comparison of Antiprogestins and SPRMs

Table: Comparison of antiprogestins and selective progesterone receptor modulators
CategoryAntiprogestinsSPRMs
Mechanism of actionAntagonists and partial agonists of progesterone receptors A and B
  • In cells with excess coactivators: SPRMs act as agonists
  • In cells with excess corepressors: SPRMs act as antagonists
Half-life18 hours32–38 hours
Time to peak90 minutes1 hour
Indications
  • Emergency contraception
  • Uterine fibroids
  • Endometriosis
  • Termination of pregnancy
  • Cervical maturation
  • Induction of labor
  • Cushing’s syndrome
  • Breast cancer
  • Meningioma
  • Emergency contraception
  • Uterine fibroids
  • Endometriosis (novel, undergoing clinical trials)
Contraindications
  • Hypersensitivity to drug or components
  • Control of hyperglycemia during pregnancy
  • Patients taking simvastatin, lovastatin, and CYP3A4 substrates
  • Vaginal bleeding
  • Endometrial atypia or endometrial cancer
Pregnancy
SPRM: selective progesterone receptor modulator
CYP: cytochrome P450

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/

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