Human Endogenous Metabolite

Etonogestrel reduces fertility through preventing the release of luteinizing hormone (LH), a reproductive hormone crucial to ovulation.
Etonogestrel also makes cervical mucus more viscous, which prevents spermatozoa from passing through and modifies the uterine lining to stop a fertilized egg from implanting into the endometrium.
Etonogestrel, a progestin, is an oxidative substrate of CYP 3A4.
Etonogestrel induces the expression of FKBP51 mRNA and protein in cultured human endometrial stromal cells (HESCs)[1].

Etonogestrel (Implanon, Nexplanon, 3-Oxodesogestrel, 3-keto-Desogestrel) is a synthetic version of progesterone, a hormone that is naturally present in female sex.

In basal medium (BM), which is a 1:1 v/v mixture of Dulbecco's MEM and Ham's F-12 without phenol red, thawed HESCs are grown to confluence with 100U/ml penicillin, 100μg/ml streptomycin, and 0.25μg/ml fungizone complex supplemented with 10% charcoal-stripped calf serum. Confluent HESCs are cultured in parallel in BM with 0.1% ethanol (vehicle control), 10 nM ethradiol or E2+100 nM progesterone, or 100 nM of either MPA (medroxyprogesterone acetate) or ETO (etonogestrel). The cultures are kept in a serum-free defined media (DM) that contains BM plus ITS+ (insulin, transferrin, selenium, and linoleic acid) premix, 5 μM of FeSO4, 50 μM of ZnSO4, 1 nM of CuSO4, 20 nM of Na2SeO3 trace elements, 50 μg/ml of ascorbic acid, and 50 ng/ml of recombinant epidermal growth factor. The cultures are kept in this medium for seven days after the serum is removed twice using 1X phosphate-buffered saline (PBS) to remove any remaining serum. After twice washing the cultures in 1X PBS to get rid of any remaining steroids, DM containing the appropriate vehicle control or steroids is added to the cultures for either six or twenty-four hours. Following their incubation periods, HESCs are stored at −70°C after being rinsed with ice-cold 1X PBS and prepared for total RNA and protein extraction.

Absorption, Distribution and Excretion
Etonogestrel administered vaginally is known to be significantly absorbed through the vaginal epithelium without increasing its concentration in urine. Orally administered Etonogestrel, on the other hand, is absorbed in the gastrointestinal tract and undergoes first-pass metabolism. Subcutaneous injection of Etonogestrel results in rapid absorption into the bloodstream with a bioavailability of 82%. It has been reported that implants release approximately 60 micrograms daily during the first 3 months, gradually decreasing thereafter to 30 micrograms by the end of the second year. Elimination of Etonogestrel and its metabolites primarily occurs via the kidneys. The apparent volume of distribution of Etonogestrel is approximately 201 liters. The clearance rate of Etonogestrel has been reported to be 7.5 liters/hour. Metabolism/Metabolites Etonogestrel is primarily metabolized in the liver by cytochrome 3A4 via hydroxylation, sulfate conjugation, and glucuronide conjugation.

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Biological Half-Life
According to reports, the elimination half-life of etoposide is 25 hours, indicating that its contraceptive effect is reversible.

Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation
Etonogestrel is available in various formulations in the United States, including the NuvaRing, a combined vaginal ring that releases 120 micrograms of Etonogestrel and 15 micrograms of ethinylestradiol daily, and subdermal implants (Implanon, Nexplanon) that release Etonogestrel at a decreasing rate over 3 years.
Based on current evidence, US experts recommend that postpartum breastfeeding women should not use combined hormonal contraceptives (such as NuvaRing) during the first 3 weeks postpartum due to concerns about increased risk of venous thromboembolism; and generally should not use combined hormonal contraceptives during the 4th week postpartum due to concerns about potential impact on breastfeeding outcomes. Postpartum breastfeeding women with other venous thromboembolism risk factors should generally not use combined hormonal contraceptives within 6 weeks postpartum. The World Health Organization guidelines are more stringent, stating that breastfeeding women should not use combined oral contraceptives within 42 days postpartum, and that the disadvantages of using this method generally outweigh the benefits during the 6 weeks to 6 months postpartum. Estrogen exposure in the initial days may lead to reduced milk production. Expert opinion suggests that the risks of progestin-only contraceptive products are generally acceptable for breastfeeding women at any postpartum time. A review of published data concluded that etamenogestrene implants appear to have a risk of approximately 0.9% lactation suppression. Low-quality evidence suggests that there may be no difference in breastfeeding rates at 6 months between immediate and delayed placement of progestin-releasing intrauterine devices. Some preliminary evidence suggests that etamenogestrene implants may delay lactation activation (stage II lactation). However, other studies have found no difference between immediate and delayed placement of etamenogestrene implants. ◉ Effects on breastfed infants: 42 women received an etamenogestrene subcutaneous implant (Implanon) between 28 and 56 days postpartum. Compared with 38 infants from similar mothers using non-hormonal intrauterine devices (IUDs), there were no statistically significant differences in disease incidence or growth rate between the two groups, except for a slightly higher but not statistically significant increase in weight gain in male infants and a higher incidence of respiratory and skin diseases in the implant group. Infants were followed up at 3 years of age; no differences were found in growth or psychomotor development.
A non-blinded randomized study of exclusively breastfeeding women compared those who received an etoposide implant within 24–48 hours postpartum (n=20) and those who received a 150 mg medroxyprogesterone acetate extended-release injection 6 weeks postpartum (n=20). There was no difference in weight gain between the two groups.
A randomized prospective study compared the growth of infants born to mothers who received an etoposide implant within 48 hours postpartum (n=50) or 6 weeks postpartum (n=50). There were no significant differences in breastfeeding rates or infant growth between the two groups in the first year of life.
A prospective non-randomized trial compared the effects of four contraceptive methods on 10 women. On day 42 postpartum, mothers began using one of the following contraceptive methods: combined ethinyl estradiol 30 mcg and levonorgestrel 150 mcg (Microvlar), an etonogestrel implant (Implanon), a levonorgestrel intrauterine system (Myrena), or a copper-containing intrauterine device (Optima). Breast milk intake was measured by administering deuterated water to the mother and by measuring the deuterium content in the infant's saliva and the number of diaper wetting sessions per day. The infant's weight and height were also measured to assess growth and development. From day 42 to day 63 postpartum, no differences were observed in breast milk intake or infant growth and development among the different contraceptive methods. A small study randomly assigned postpartum women to two groups: one group received an etonogestrel implant (Implanon) within 48 hours postpartum (n = 12), and the other group did not use any contraception for the first 6 weeks postpartum (n = 12). Breast milk intake was measured at 48 hours postpartum and on day 29 postpartum. There was no difference in breast milk intake between the two groups, nor in neonatal weight gain during the follow-up period.
◉ Effects on Lactation and Breast Milk
42 women received an etoposide subcutaneous implant (Implanon) between 28 and 56 days postpartum. There were no differences in breast milk volume, lactose, protein, or fat content compared to 38 similar mothers using non-hormonal intrauterine devices. There was no significant difference in the duration of lactation between the two groups, with a mean of 421 days in the implant group and 423 days in the IUD group.
A non-blinded randomized study compared exclusive breastfeeding women who received an etoposide implant 24 to 48 hours postpartum (n = 20) with those who received a 150 mg extended-release medroxyprogesterone acetate injection at 6 weeks postpartum (n = 20). Exclusive breastfeeding rates were similar in both groups at 6 and 12 weeks postpartum. A randomized controlled trial compared the effects of etoposide implantation 1-3 days postpartum (n = 35) versus etoposide implantation 4-8 weeks postpartum (n = 34). The study measured several outcome measures: time to lactation stage II, lactation failure rate, formula supplementation, and milk composition at 6 weeks postpartum. There were no differences in any outcome measures between the two groups. One mother successfully breastfed her newborn, and the infant grew well. On day 39 postpartum, an etoposide implant (Nexplanon) was implanted. By day 70 postpartum, the mother reported reduced breast milk production, infant weight loss, and a drop in growth percentile from the 44th percentile to the 6th percentile. Five weeks later, the mother switched entirely to formula feeding. The authors requested a report from the U.S. Food and Drug Administration (FDA) regarding etoposide and found a similar case of reduced breast milk production. Based on a review of four published studies, the authors estimated that the probability of etoposide implants suppressing lactation is approximately 0.9% (range 0.2% to 5.4%). A randomized, non-blinded trial compared the effects of etoposide implants (brand unspecified) in postpartum women aged 14 to 24 years before discharge or 6 weeks postpartum. At 3 and 6 months postpartum, women who received immediate implants had slightly higher breastfeeding rates, but the difference was not statistically significant. A randomized prospective study compared the growth of infants born to mothers who received etoposide implants within 48 hours postpartum (n=50) or 6 weeks postpartum (n=50). There was no significant difference in breastfeeding rates between the two groups in the first year of life. A study in Malawi compared breastfeeding rates in women who received immediate postpartum implants of etoposide (n=28) or levonorgestrel (n=112). Mothers chose their implantation method and underwent a 2-year postpartum follow-up. Most women continued breastfeeding for 2 years. There were no differences between the two groups in the rate of exclusive breastfeeding at 6 months and the proportion of women continuing to breastfeed until 2 years of age. A study of women intending to breastfeed randomly assigned them to two groups: one received a progestin implant (presumably etoposide) in the delivery room, and the other received it within 24 to 48 hours postpartum. There was no significant difference in the time to reach stage II lactation between the two groups. A small, non-randomized, prospective pilot study compared the time to lactation activation in women who received an etoposide implant (Nexplanon; n = 8) and women who did not use contraception (n = 24). Women who received etoposide implants experienced a delayed time to lactation activation, as determined by biochemical assays. A non-inferiority study randomly assigned postpartum women to two groups, receiving etoposide implants 0 to 2 hours postpartum (n = 35) or 24 to 48 hours postpartum (n = 34). There was no significant difference in the time required to reach stage II lactation between the two groups. Another study randomly assigned postpartum women to three groups, with etoposide implanted within 30 minutes of placental delivery, 24 to 72 hours postpartum, or 6 weeks and beyond postpartum. There was no significant difference in the time required to reach lactation stage II among the groups, with a mean time of 62 hours. The duration of breastfeeding, exclusive breastfeeding, implant satisfaction, and reports of excessive or irregular bleeding were similar across groups. One woman who received Nexplanon implantation 2 months postpartum and began breastfeeding reported persistent galactorrhea. The galactorrhea persisted for 2 years until the Nexplanon implant was removed. Her galactorrhea symptoms improved at 1 month and 7 months postpartum. Protein Binding: Etoposide is highly bound to plasma proteins, primarily albumin, followed by sex hormone-binding globulin. Approximately 96-99% of the administered dose of etoposide is protein-bound.

[1]. Dionne D. Maddox, et al. Etonogestrel (Implanon), Another Treatment Option for Contraception. P T. 2008 Jun; 33(6): 337–347.

[2]. Ozlem Guzeloglu Kayisli, et al. Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding. PLoS One. 201 .

Etonogestrel is a 17β-hydroxysteroid, 3-oxo-Δ⁴ steroid, and terminal alkyne compound. It is a contraceptive, progestin, and female contraceptive. The Etonogestrel molecule is 3-ketodisogestene or 19-nortestosterone, a synthetic bioactive metabolite of the progestin disogestene. The first product containing Etonogestrel was developed by Organon, a subsidiary of Merck, and approved by the U.S. Food and Drug Administration (FDA) in 2001. Etonogestrel is a progestin. Etonogestrel is the synthetic form of the natural female sex hormone progesterone. Etonogestrel binds to cytoplasmic progesterone receptors in the reproductive system, subsequently activating progesterone receptor-mediated gene expression. Due to a negative feedback mechanism, the release of luteinizing hormone (LH) is inhibited, leading to ovulation suppression and changes in cervical mucus and the endometrium. See also: ethinylestradiol; Etonogestrel (ingredient).

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Drug Indications
Etonogestrel is a long-acting reversible contraceptive administered as a subdermal implant. It is known to be effective in postpartum implantation (including in breastfeeding women). Etonogestrel is a component of long-acting contraceptive implants and prevents pregnancy. The contraceptive effect of the implant lasts for up to 5 years.
FDA Label
Mechanism of Action
Etonogestrel binds with high affinity to progesterone and estrogen receptors in target organs. Target organs include the female reproductive tract, mammary glands, hypothalamus, and pituitary gland. Once bound to cells, the drug alters the synthesis of various proteins, thereby reducing levels of gonadotropin-releasing hormone and luteinizing hormone.

C22H28O2

324.4565

324.208

C, 81.44; H, 8.70; O, 9.86

54048-10-1

54048-10-1

6917715

White to off-white solid powder

1.1±0.1 g/cm3

473.1±45.0 °C at 760 mmHg

182-184ºC

201.1±21.3 °C

0.0±2.7 mmHg at 25°C

1.575

4.22

1

2

2

24

677

6

O([H])[C@@]1(C#C[H])C([H])([H])C([H])([H])[C@@]2([H])[C@]3([H])C([H])([H])C([H])([H])C4=C([H])C(C([H])([H])C([H])([H])[C@]4([H])[C@@]3([H])C(=C([H])[H])C([H])([H])[C@@]21C([H])([H])C([H])([H])[H])=O

GCKFUYQCUCGESZ-BPIQYHPVSA-N

InChI=1S/C22H28O2/c1-4-21-13-14(3)20-17-9-7-16(23)12-15(17)6-8-18(20)19(21)10-11-22(21,24)5-2/h2,12,17-20,24H,3-4,6-11,13H2,1H3/t17-,18-,19-,20+,21-,22-/m0/s1

(8S,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-17-hydroxy-11-methylidene-2,6,7,8,9,10,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-3-one

ORG 3236; ORG3236; ORG-3236; Implanon; Etonogestrel; nexplanon; 3-keto-desogestrel, 3-ketodesogestrel, 3-oxo desogestrel, 3-oxodesogestrel

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 50~65 mg/mL (154.1~200.3 mM)
Ethanol: 65 mg/mL (~200.3 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)