Gestodene

Gestodene (GSD) is a synthetic progestogen used in combined oral contraceptives. It is available in Europe but not the US.

Tags
gestodene

Identifiers

Abbreviation

GSD

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References

Names

  • Δ15-norgestrel
  • 15-dehydronorgestrel
  • 17α-ethynyl-18-methylestra-4,15-dien-17β-ol-3-one

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References

CASRN

60282-87-3

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References

PubChem CID

3033968

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ECHA InfoCard

100.056.478

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UNII

1664P6E6MI

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KEGG Entry Number

D04316

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Wikipedia Entry Name

Gestodene

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ChEBI ID

CHEBI:135323

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ChEMBL ID

CHEMBL1213583

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ChemSpider ID

2298532

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ATC Code(s)

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Toxicology

GHS Hazard Code(s)

Class Category Code Description
Reproductive Toxicity 2 H361 Suspected of damaging fertility or the unborn child
Carcinogenicity 2 H351 Suspected of causing cancer if inhaled
Reproductive Toxicity 1A H360 May damage fertility or the unborn child
Reproductive Toxicity, Effects On or Via Lactation H362 May cause harm to breast-fed children

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Side Effects

Headaches, breast tension, acne, nervousness, depression, dizziness

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References

  1. Stanczyk, F. Z.; Archer, D. F., Gestodene: a review of its pharmacology, potency and tolerability in combined contraceptive preparations. Contraception 2014, 89 (4), 242-52.
  2. (View all citations for this reference)

LD50

mouse oral: 6 g/kg

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Safety Profile Overview

Oral contraceptives containing gestodene are considered a safe, effective, well-tolerated option.

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References

  1. Stanczyk, F. Z.; Archer, D. F., Gestodene: a review of its pharmacology, potency and tolerability in combined contraceptive preparations. Contraception 2014, 89 (4), 242-52.
  2. (View all citations for this reference)

Biochemistry & Pharmacology

Progesterone Receptor Activity

Agonist

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References

Androgen Receptor Activity

Reported as agonist with high relative binding affinity and no antagonist activity, but Stanczyk notes that data consistent with low androgenic potential and strong antagonist effects demonstrated in vitro.

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References

  1. Africander, D.; Verhoog, N.; Hapgood, J. P., Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76 (7), 636-52.
  2. (View all citations for this reference)
  3. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
  4. (View all citations for this reference)
  5. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
  6. (View all citations for this reference)
  7. Stanczyk, F. Z.; Archer, D. F., Gestodene: a review of its pharmacology, potency and tolerability in combined contraceptive preparations. Contraception 2014, 89 (4), 242-52.
  8. (View all citations for this reference)

Estrogen Receptor Activity

Antagonist

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References

  1. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
  2. (View all citations for this reference)
  3. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
  4. (View all citations for this reference)
  5. Africander, D.; Verhoog, N.; Hapgood, J. P., Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76 (7), 636-52.
  6. (View all citations for this reference)

Glucocorticoid Receptor Activity

Reported as "weak" (Africander, Kuhl) and "active" (Ruan, Lello) agonist

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References

  1. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of dienogest. Maturitas 2012, 71 (4), 337-44.
  2. (View all citations for this reference)
  3. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
  4. (View all citations for this reference)
  5. Africander, D.; Verhoog, N.; Hapgood, J. P., Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76 (7), 636-52.
  6. (View all citations for this reference)
  7. Kuhl, H., Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005, 8 Suppl 1, 3-63.
  8. (View all citations for this reference)

Mineralocorticoid Receptor Activity

Binds. Activity reports vary slightly: reported as an antagonist (Ruan, Lello, Kuhl), while Africander reports that some antagonist activity is seen in rat models and Stanczyk claims it to be relatively weak compared to progesterone.

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References

  1. Africander, D.; Verhoog, N.; Hapgood, J. P., Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids 2011, 76 (7), 636-52.
  2. (View all citations for this reference)
  3. Kuhl, H., Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005, 8 Suppl 1, 3-63.
  4. (View all citations for this reference)
  5. Stanczyk, F. Z.; Archer, D. F., Gestodene: a review of its pharmacology, potency and tolerability in combined contraceptive preparations. Contraception 2014, 89 (4), 242-52.
  6. (View all citations for this reference)
  7. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
  8. (View all citations for this reference)
  9. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
  10. (View all citations for this reference)
  11. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
  12. (View all citations for this reference)

Excretion

Only 1% excreted unchanged in urine.

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References

  1. Besse, J. P.; Garric, J., Progestagens for human use, exposure and hazard assessment for the aquatic environment. Environ. Pollut. 2009, 157 (12), 3485-3494.
  2. (View all citations for this reference)

Apparent Volume of Distribution

0.7 L/kg

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Cmax

5.6 ng/L from 0.1 mg gestodene/0.03 mg ethinyl estradiol tablet administered orally.
1.0 ng/mL from 0.025 mg gestodene administered orally.
3.6 ng/mL from 0.075 mg gestodene administered orally.
7.0 ng/mL from 0.125 mg gestodene administered orally.

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Tmax

0.5 h from 0.1 mg gestodene/0.03 mg ethinyl estradiol tablet administered orally.
1.4-1.9 h for oral administration of 0.025, 0.075, or 0.125 mg gestodene tablets.

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Enzyme Interactions

  • CYP3A4: inducer (PubChem, Toxnet), inhibitor (KEGG, Laine et al.)
  • CYP3A7, CYP3A5, CYP2C19: inhibitor

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References

  1. KEGG: Gestodene (View all citations for this reference)
  2. PubChem: Gestodene (View all citations for this reference)
  3. Laine, K.; Yasar, U.; Widen, J.; Tybring, G. A Screening Study on the Liability of Eight Different Female Sex Steroids to Inhibit CYP2C9, 2C19 and 3A4 Activities in Human Liver Microsomes. Pharmacol. Toxicol. 2003, 93 (2), 77–81.
  4. (View all citations for this reference)
  5. Toxnet: Gestodene. (View all citations for this reference)

Inhibition of Ovulation

0.04 mg/day

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References

  1. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
  2. (View all citations for this reference)

Transformation of Endometrium

2-3 mg/cycle

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References

  1. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
  2. (View all citations for this reference)

Menstrual Delay

~0.2 mg/day

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References

  1. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
  2. (View all citations for this reference)

Metabolites

Name
Structure
Notes
structure

Lower activity for progesterone receptor than gestodene.

structure

Significantly reduced progestational activity compared to gestodene. Selectively activates ERα.

structure

Significantly reduced progestational activity compared to gestodene. Selectively activates ERα.

Impurities

Name
Structure
CASRN
Other Names & Identifiers
structure

  • BP Gestodene Impurity L
  • 13-ethyl-17-hydroxy-18,19-dinor-17α-pregna-5,15-dien-20-yn-3-one

structure

  • BP Gestodene Impurity K
  • 13-ethyl-3,17-dihydroxy-18,19-dinor-17α-pregna-1,3,5(10),15-tetraen-20-yn-6-one

structure

  • BP Gestodene Impurity J
  • 13-ethylspiro(18,19-dinor-17α-pregna-5,15-dien-20-yne-3,2'-[1,3]dioxolan)-17-ol and 13-ethylspiro(18,19-dinor-17α-pregna-5(10),15-dien-20-yne-3,2'-[1,3]dioxolan)-17-ol

structure

  • BP Gestodene Impurity I
  • 13-ethyl-17-hydroxy-5-methoxy-18,19-dinor-5α,17α-pregn-15-en-20-yn-3-one

structure

  • BP Gestodene Impurity H
  • 13-ethyl-3-ethynyl-18,19-dinor-17α-pregna-3,5,15-trien-20-yn-17-ol