Gestodene

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

Tags
gestodene
MOL SDF CML

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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References

  1. PubChem: Gestodene (View all citations for this reference)

ECHA InfoCard

100.056.478

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References

  1. ECHA InfoCard: Gestodene (View all citations for this reference)

DrugBank Accession Number

DB06730

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References

  1. DrugBank: Gestodene
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)

UNII

1664P6E6MI

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References

  1. UNII: Gestodene (View all citations for this reference)

KEGG Entry Number

D04316

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References

  1. KEGG: Gestodene (View all citations for this reference)

Wikipedia Entry Name

Gestodene

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References

  1. Wikipedia: Gestodene (View all citations for this reference)

ChEBI ID

CHEBI:135323

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References

  1. ChEBI: Gestodene (View all citations for this reference)

ChEMBL ID

CHEMBL1213583

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References

  1. ChEMBL: Gestodene (View all citations for this reference)

ChemSpider ID

2298532

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References

  1. ChemSpider: Gestodene (View all citations for this reference)

ATC Code(s)

info

Physical & Chemical Properties

Molecular Formula

C21H26O2

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References

Molecular Weight

310.44 g/mol

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References

Appearance

Crystals

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References

  1. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)

Melting Point

197.9° C

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References

  1. ChemIDPlus: A Toxnet Database. Gestodene. (View all citations for this reference)
  2. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)
  3. Toxnet: Gestodene. (View all citations for this reference)

Solubility

8.11 mg/L water at 25 °C

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References

  1. PubChem: Gestodene (View all citations for this reference)

Specific Optical Rotation

-185.7 (for the sodium D line)

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References

  1. PubChem: Gestodene (View all citations for this reference)
  2. Toxnet: Gestodene. (View all citations for this reference)

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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References

  1. ECHA InfoCard: Gestodene (View all citations for this reference)

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)

Mutagenicity

Not found to be mutagenic in the Ames Salmonella/microsome direct plate incorporation protocol.

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References

  1. Lang, R.; Reimann, R. Studies for a Genotoxic Potential of Some Endogenous and Exogenous Sex Steroids. I. Communication: Examination for the Induction of Gene Mutations Using the Ames Salmonella/microsome Test and the HGPRT Test in V79 Cells. Environ. Mol. Mutagen. 1993, 21 (3), 272–304. (View all citations for this reference)

LD50

mouse oral: 6 g/kg

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References

  1. PubChem: Gestodene (View all citations for this reference)

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)
  2. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
    3. (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)
  4. 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.
    5. (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)
  2. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    3. (View all citations for this reference)
  3. 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.
    4. (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)
  2. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    3. (View all citations for this reference)
  3. 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.
    4. (View all citations for this reference)
  4. Kuhl, H., Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005, 8 Suppl 1, 3-63.
    5. (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)
  2. Kuhl, H., Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric 2005, 8 Suppl 1, 3-63.
    3. (View all citations for this reference)
  3. 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.
    4. (View all citations for this reference)
  4. Lello, S., Nomegestrol Acetate Pharmacology, Safety Profile and Therapeutic Efficacy. Drugs 2010, 70 (5), 541-559.
    5. (View all citations for this reference)
  5. Ruan, X.; Seeger, H.; Mueck, A. O., The pharmacology of nomegestrol acetate. Maturitas 2012, 71 (4), 345-53.
    6. (View all citations for this reference)
  6. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
    7. (View all citations for this reference)

Bioavailability

99%

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References

  1. Schindler, A. E.; Campagnoli, C.; Druckmann, R.; Huber, J.; Pasqualini, J. R.; Schweppe, K. W.; Thijssen, J. H. H., Classification and pharmacology of progestins. Maturitas 2003, 46, 7-16.
    2. (View all citations for this reference)
  2. Stanczyk, F. Z., Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception. Rev. Endocr. Metab. Disord. 2002, 3 (3), 211-224. (View all citations for this reference)
  3. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)
  4. PubChem: Gestodene (View all citations for this reference)
  5. Toxnet: Gestodene. (View all citations for this reference)

Elimination Half-Life (t1/2)

12-14 h, 16-18 h

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References

  1. Stanczyk, F. Z., Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception. Rev. Endocr. Metab. Disord. 2002, 3 (3), 211-224. (View all citations for this reference)
  2. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e, 2011 > Estrogens and Progestins. Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann.
    3. (View all citations for this reference)
  3. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)
  4. PubChem: Gestodene (View all citations for this reference)
  5. Toxnet: Gestodene. (View all citations for this reference)

Serum Protein Binding

75% to SHBG, 24% to albumin, 0.6% free (exact percentages vary depending on treatment)

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References

  1. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)
  2. PubChem: Gestodene (View all citations for this reference)
  3. Rebar, R. W.; Zeserson, K., CHARACTERISTICS OF THE NEW PROGESTOGENS IN COMBINATION ORAL-CONTRACEPTIVES. Contraception 1991, 44 (1), 1-10.
    4. (View all citations for this reference)
  4. Toxnet: Gestodene. (View all citations for this reference)

Metabolism

Hepatic, primarily by CYP3A4

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References

  1. PubChem: Gestodene (View all citations for this reference)
  2. Toxnet: Gestodene. (View all citations for this reference)
  3. Nanda, K.; Stuart, G. S.; Robinson, J.; Gray, A. L.; Tepper, N. K.; Gaffield, M. E. Drug Interactions between Hormonal Contraceptives and Antiretrovirals. AIDS 2017, 31 (7), 917–952. (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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References

  1. PubChem: Gestodene (View all citations for this reference)

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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References

  1. Toxnet: Gestodene. (View all citations for this reference)

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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References

  1. Toxnet: Gestodene. (View all citations for this reference)

Clearance

0.8 mL/min/kg

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References

  1. PubChem: Gestodene (View all citations for this reference)
  2. Toxnet: Gestodene. (View all citations for this reference)

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)
  4. 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
3α,5α-tetrahydrogestodene
structure

Lower activity for progesterone receptor than gestodene.

5α-dihydrogestodene
structure

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

3β,5α-tetrahydrogestodene
structure

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

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Impurities

Name
Structure
CASRN
Other Names & Identifiers
Δ5(6)-Gestodene
structure

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

Aromatic 6-Keto-Gestodene
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

Gestodene Ketal
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

5-Methoxy-Gestodene
structure

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

Diethynyl-Gestodene
structure

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

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