Altrenogest - C21H26O2
By Gabriella Grasso
Table of Contents
How Altrenogest (C21H26O2 ) works :
This toxicant is not an element, rather it is a synthetic progesterone agonist that is utilized in veterinary medicine to suppress estrus in horses and swine (PubChem, 2024)
It mimics the effects of progesterones by preparing and maintaining the reproductive tract of female horses for implantation and pregnancy (Michnik,. et al, 2007)
Besides these mimic effects, this toxicant's effects are promoted by it's interaction with the progesterone receptor partial binding to other steroid receptors (Michnik,. et al, 2007)
This toxicant has an inhibitory effect on the luteinizing hormone, which is needed for the synthesis of androstenedione by the ovarian thecal cells for ovulation and the corpus luteum (Schriefer, 2007)
It inhibits the release of the luteinizing hormone from the anterior pituitary (Bradecamp, 2007)
It requires daily dosing to see the intended effects in horses, and after a period of 15 to 18 days of daily dosing, the corpus luteum will regress, meaning that the only source of progesterone to suppress estrus is the exogenous progesterone (Bradecamp, 2007).
Alternative Names of C21H26O2
Altrenogest
(PubChem, 2024)
Ally Trenbolone
(PubChem, 2024)
Ovamed
(PubChem, 2024)
Altren
(PubChem, 2024)
Regumate
(PubChem, 2024)
17a-allyl-17b-hydroxyestra-4,9,11-trien-3-one
(PubChem, 2024)
Most Common Present and Recent Past Uses of is C21H26O2
Administered to female horses, also known as mares, for :
Help regulating estrus synchronization (Storer, et al., 2009) *
Maintain equine Pregnancies (Storer, et al., 2009) *
Estrus suppression (Storer, et al., 2009) *
Ovulation (Storer, et al., 2009) *
There is suspicious misuse of this drug for male horses, as it is intended for mares not geldings or stallions (Michnik, et al., 2007)
Male competition horses, including geldings and stallions, are wrongfully given this drug to suppress their behavior through the drug's potential anabolic effects (Michnik, et al., 2007)
Regumate was the first C21H26O2 drug released in 1987 and the most recently C21H26O2 approved drugs are Ovamed in 2012 and Altren in 2017 (U.S Food and Drug Administration, 2023)
Undesirable equine behaviors that some intend to suppress include:
Less cooperative (Storer, et al., 2009) *
Less attentive to tasks (Storer, et al., 2009) *
Hyper-excitable (Storer, et al., 2009) *
Sensitivity to touch (Storer, et al., 2009) *
Chemical structure of C21H26O2 (PubChem, 2024)
C21H26O2 has a structural relation to the anabolic steroid trenbolone, with a 3-keto-4,9,11-triene steroid nucleus, meaning that altrenogest is a candidate with anabolic potential (Machnik, et al., 2007)
Boiling Point = 495.6±45.0 °C at 760 mmHg (ChemSpider)
Density = 1.1±0.1 g/cm3 (ChemSpider)
Chemical Structure and Chemical Properties
C21H26O2 is a 3-hydroxy steroid with a molecular weight of 310.4 g/mol that is a synthetic progesterone (PubChem, 2024)
Altrenogest is regarded as a derivative of the C19-steroid nortestosterone and differs by two double bonds in positions 9 and 11 and an allyl group at C17 (Machnik, et al., 2007)
(Machnik, et al., 2007)
Luteinizing Hormone (LH)
The hormone that altrenogest has an inhibitory effect on
What is it: A glycoprotein hormone that is co-secreted with follicle-stimulating hormone by the gonadotrophin cells (Nedresky, D., and Singh, G., 2022)
Where is LH produced: in the adenohypophysis, which is the anterior pituitary (Nedresky, D., and Singh, G., 2022)
What organ systems is LH involved in: the neurological pathway and reproductive organ systems in males and females
The neurological pathway includes the hypothalamus, pituitary gland, and gonads (Nedresky, D., and Singh, G., 2022)
How does this hormone work in the neurological pathway: LH release is stimulated by the gonadotropin-releasing hormone, and is inhibited by estrogen in females and males in testosterone (Nedresky, D., and Singh, G., 2022)
Functions: These differ in men and women
In both sexes:
Contributes to the maturation of primordial germ cells (Nedresky, D., and Singh, G., 2022)
In males:
Signals leydig cells of the testes to produce testosterone (Nedresky, D., and Singh, G., 2022)
In females:
Triggers the creation of steroid hormones from the ovaries, ovulation, and the release of progesterone post ovulation by the corpus luteum (Nedresky, D., and Singh, G., 2022)
Regulates the length and order of the menstrual cycle by having roles in ovulation and egg implantation in the uterus (Nedresky, D., and Singh, G., 2022)
Routes of Exposure to Humans
Humans are not the intended species for C21H26O2 administration, and they can experience adverse health affects when exposed
This drug is given to horses orally, which contributes to the ways in which humans can experience exposure (Nie, 2007)
Moreover, since this drug is given to horses, it is most likely that those who work and/or participate in the equine industry will be most likely prone to exposure
The required daily dosing of this drug also increases chances of exposure (Nie, 2007)
The labeled dose, which is in an oil solution, given to horses is 0.044 mg/kg with 1 ml per 110 lb of the animal's body weight (Nie, 2007)
Routes of exposure include:
Via skin (Nie, 2007)
The oily nature of C21H26O2 combined with its required daily dosing increases chances of exposure through the skin as it often spills, squirts out, and/or leaks (Nie, 2007)
Exposure can occur even if a human is wearing gloves as latex gloves do not provide adequate protection (U.S Food and Drug Administration, 2023)
Via contaminated objects and/or surfaces (U.S Food and Drug Administration, 2023)
If consumed orally, C21H26O2 is acutely toxic to humans (PubChem, 2024)
Distribution and Metabolism
Distribution:
Altrenogest is given to horses orally in an oil-based solution, which than acts upon the luteinizing hormone to suppress estrus in mares as it has an inhibitory effect (Schriefer, 2007)
Since this toxicant targets the luteinizing organ, which is produced in the pituitary glands and exists in the neurological pathway, the targeted system is the neurological pathway in both humans and horses (Nedresky, D., and Singh, G., 2022)
Researchers found that a glucuronide conjugate of altrenogest could be detected in horse urine after administration, inferring that altrenogest is distributed to the urinary pathway to be excreted out after undergoing metabolization (Lampinen-Salomonsson,. et al, 2006).
Metabolism:
The main metabolic route of altrenogest in horses was through conjugation with glucuronic acid and sulfate (Lampinen-Salomonsson,. et al, 2006).
There were no phase I metabolites found while studying the metabolism of altrenogest in horses (Lampinen-Salomonsson,. et al, 2006).
Adverse Health Consequences for Humans
Men and women can be affected by C21H26O2 as it inhibits the luteinizing hormone, which is hormone is needed for the synthesis of androstenedione, therefore causing reproductive adverse effects (Bradecamp, 2007)
These inhibitory effects can potentially harm fertility and/or damage an unborn child (PubChem, 2024)
The U.S Food and Drug Administration announced that there are potential health risks for humans who are exposed to C21H26O2 products with reports of adverse health effects from 115 women and 22 men between 1987 and 2018 (U.S Food and Drug Administration, 2023)
The U.S Food and Drug Administration acknowledges that reports of exposure are presumably severely under-reported due to the lack of education and research encompassing this toxicant (U.S Food and Drug Administration, 2023)
Males can experience decreased libido (U.S Food and Drug Administration, 2023)
Women can experience abnormal menstrual cycle effects including changes in bleeding and patterns (U.S Food and Drug Administration, 2023)
Both men and women can experience headaches, fever, vomiting, skin rashes, abnormal pain, and diarrhea (U.S Food and Drug Administration, 2023)
Evaluation on Injectable Sustained Release Progestin Formulations for Suppression of Estrus and Ovulation in Mares *
Experimental Study by William A. Storer, Donald L. Thompson Jr., Richard M. Gilley, and Patrick J. Burns
Reasons for Conducting Study *:
Daily administration of synthetic progestins can be impractical in regards to seeing the intended results of preventing the expression of estrus in race, show, and broodmares for periods of weeks and up to months (Storer,. et al, 2009)*
New discoveries of altrenogest drugs (C21H26O2) that are in controlled-release delivery systems potentially offer single administration products, which will replace prolonged daily treatment protocols (Storer,. et al, 2009)*
Single-administration products reduce risk of exposure, reduce labor, enable less handling stress, and provide greater flexibility for veterinarians in maintaining compliance on farms and in show rings (Storer,. et al, 2009)*
To determine the effectiveness of three different sustained-release injectable formulations of altrenogest in equine pregnancy maintenance, the inhibition of estrus behavior, and mare ovulation (Storer,. et al, 2009)*
Experimental Approach *:
31 mares were subjects in this experiment to test the effectiveness of 3 sustained-release injectable formulations of altrenogest (C21H26O2) and one formulation of medroxyprogesterone acetate (MPA) for long term suppression of estrus and ovulation (Storer,. et al, 2009)*
Formulations included:
Control with no active ingredients and no form or vehicle for administration (Storer,. et al, 2009)*
LA 150 1.5 mL with the active ingredient being Altrenogest in the form of BioRelease LA Altrenogest solution with the Mg total being 225 Mg and the volume being 1.5 mL (Storer,. et al, 2009)*
LA 150 3 mL with the active ingredient being Altrenogest in the form of BioRelease LA Altrenogest solution with the Mg total being 450 Mg and the volume being 3.0 mL (Storer,. et al, 2009)*
MP 500 with the active ingredient being Altrenogest in the form of Lactide-glycolide microparticles with the Mg total being 500 Mg and the volume being 7.0 mL (Storer,. et al, 2009)*
Medroxyprogesterone acetate (MPA) with the active ingredient being MPA in the form of aqueous suspension with the Mg total being 1000 Mg and the volume being 5.0 mL (Storer,. et al, 2009)*
Medroxyprogesterone acetate (MPA) is a synthetic progestin that is commonely prescribed for equine estruss supression, but is not documented in controlled experiments, therefore, it was included for comparison against the altrenogest solutions (Storer,. et al, 2009)*
Luteolysis, which is the loss of function of the corpus luteum and its involvement in ovulation, was induced by injection of prostaglandin-F2a on day 0 of the experiment to be followed by the different injections of the altrenogest solutions (Storer,. et al, 2009)*
Mares started experiment in mid-diestrus simultaneously with this induction of luteolysis using prostaglandin-F2a (Storer,. et al, 2009)*
Those who displayed diestrus at the onset of estrus detection and had progesterone concentrations above 1 ng/mL were given Lutalyse at that time while those we had not responded by entering estrus 5 days later were re-treated (Storer,. et al, 2009)*
5 treatments were administered on day 0 with six mares per treatment group (Storer,. et al, 2009)*
Except for the control group, the sample size was 7 mares, and they received no injections (Storer,. et al, 2009)*
Mares were assessed for estrus by daily teasing with a stallion, and once treated, their ovaries were scanned every other day until a 25-mm or greater follicle was detected, and if it was detected, daily scanning began (Storer,. et al, 2009)*
Blood samples were taken via jugular venipuncture before each ultrasound examination for later hormonal assessment (Storer,. et al, 2009)*
After a mare returned to estrus and ovulated, or ovulated a large, dominant follicle without showing estrus, monitoring stopped (Storer,. et al, 2009)*
Plasma luteinizing hormone (LH) concentrations were measured by a double-antibody radioimmunoassay, and these concentrations were measured with commercially available reagents (Storer,. et al, 2009)*
Results of Experimental Study *
All altrenogest formulations were found to be effective at delaying the onset of estrus and ovulation, but the formulation with the longest lasting inhibitory effect was the MP 500 formulation (Storer,. et al, 2009)*
This formulation's active ingredient is altrenogest, consisting of 500 mg altrenogest encapsulated in lactide-glycolide micro-particles (Storer,. et al, 2009)*
The MP 500 formulation inhibited onset of estrus by at least 25 days and considerably longer in some mares (Storer,. et al, 2009)*
Since this formulation onset estrus by the longest, and that is the intended use of this drug, the MP 500 formulation should be used in cases where long term estrus suppression is wanted in performance mares (Storer,. et al, 2009)*
The LA 150 3 mL formulation with 450 mg altrenogest inhibited onset of estrus for roughly 15 days, which indicates there is more rapid release (Storer,. et al, 2009)*
The difference in timelines (15 days for LA 150 3 mL vs at least 25 days for MP 500) for the inhibition of the onset of estrus signifies that LA 150 3 mL should be used for shorter-term suppression of estrus and ovulation, whereas MP 500 should be used for longer-term suppression (Storer,. et al, 2009)*
(Storer,. et al, 2009)*
Experimental Study's Correlation to Altrenogest's Adverse Health Effects for Humans
This study exposed how different formulations of altrenogest, given in different vehicles/forms and concentrations, effectively suppressed estrus in female horses at different timelines (shorter term suppression vs longer term suppression)
Humans and horses both need the luteinizing hormone (LH) for the creation of steroid hormones from the ovaries, for ovulation, the release of progesterone post ovulation, and to regulate the order and length of the menstrual cycle. Since horses have significantly larger masses than humans, they have different amounts of tolerable dosages of altrenogest. There has been no tests on the effects of altrenogest on the human reproductive system as this is a veterinary drug intended for horses. With horses having larger masses than humans with different tolerances to altrenogest dosages, humans will most likely experience adverse health effects in regards to their reproductive systems as people do not have enough mass to prevent the inhibitory effects on LH caused by altrenogest.
What this study does for toxicology*:
This study and original research is important for toxicology as it helps those in the equine world and veterinary medicine choose a proper altrenogest formulation for estrus suppression in horses, specifically if they prefer longer term or shorter term estrus suppression. By exposing which injectable sustained release altrenogest formulations have longer and shorter estrus suppression timelines, there can be reductions made in regards to exposure risks as the specific formulation chosen can reduce the amount of daily dosing required. Daily dosing of altrenogest increases the potential risk of exposure because there are greater opportunities for accidental leaks and spills, which can seep through human skin even if an individual is wearing latex gloves. Even if altrenogest is exposed to humans through the skin or on contaminated objects, both men and women can still face reproductive system damages due to the inhibitory effects on LH caused by altrenogest. Therefore, decreasing the amount of daily dosing needed while still seeing the intended outcomes in horses can effectively reduce possibilities of reproductive damage in humans.
Proposed Actions
All individuals, male or female, who administer altrenogest formulations to their horses should be incredibly cautious of the harmful reproductive side effects that can occur after repeated exposure to altrenogest. There should be more research done on how this toxicant specifically inflicts harm upon humans, their reproductive system, and neurological pathway, since they are more prone to negative side effects as they are not the intended species of this veterinary drug. There should be increased education on the harmfulness of this drug at major horse show events, horse races, and veterinary clinics as an effort to help reduce accidental exposures and bolster people's awareness. Barns that utilize altrenogest should be given educational lessons on how to properly clean surfaces that have been contaminated, proper clean-up and removal of altrenogest, as well as how to shield one's self from accidental exposure. There should be a limit on the age of those who administer this drug in order to prevent lifelong reproductive and fertility issues. When selling this drug, there should be more information given on the routes of exposure as it can be through contaminated objects and/or through skin/latex gloves. The FDA should conduct more research on the potential routes of metabolism and distribution throughout the bodies of horses and humans to better understand how different amounts of altrenogest equate to different symptoms and effects in humans. There is limited research on the effects of altrenogest on humans since there is not a clear way of conducting that research in an ethical way, therefore, researchers, veterinarians, and the FDA should work in unison to uncover how they can learn more about the effects on humans with acceptable and safe research procedures.
Works Cited:
Bradecamp, E.A. (2007) CHAPTER 3 - Estrous Synchronization. In, Samper,J.C. et al. (eds), Current Therapy in Equine Reproduction. W.B. Saunders, Saint Louis, pp. 22–25.
ChemSpider Altrenogest | C21H26O2 . ChemSpider. Available: https://www.chemspider.com/Chemical-Structure.8216634.html [Accessed 15 April 2024]
U.S Food and Drug Administration (2023) Potential Health Risks to People Exposed to Altrenogest Products for Horses or Pigs. FDA. Available: https://www.fda.gov/animal-veterinary/product-safety-information/potential-health-risks-people-exposed-altrenogest-products-horses-or-pigs [Accessed 15 April 2024]
Lampinen-Salomonsson, M. et al. (2006) Detection of altrenogest and its metabolites in post administration horse urine using liquid chromatography tandem mass spectrometry—increased sensitivity by chemical derivatisation of the glucuronic acid conjugate. Journal of Chromatography B, 833, 245–256.
Machnik, M. et al. (2007) Pharmacokinetics of altrenogest in horses. Vet Pharm & Therapeutics, 30, 86–90.
Nedresky, D. and Singh, G. (2024) Physiology, Luteinizing Hormone. In, StatPearls. StatPearls Publishing, Treasure Island (FL).
Nie, G.J. (2007) CHAPTER 4 - Estrous Suppression. In, Samper,J.C. et al. (eds), Current Therapy in Equine Reproduction. W.B. Saunders, Saint Louis, pp. 26–31.
PubChem (2024) Altrenogest. National Center for Biotechnology Information. Available: https://pubchem.ncbi.nlm.nih.gov/compound/10041070 [Accessed 15 April 2024]
Schriefer, J. (2007) Luteinizing Hormone. In, Enna,S.J. and Bylund,D.B. (eds), xPharm: The Comprehensive Pharmacology Reference. Elsevier, New York, pp. 1–4.
Storer, W.A. et al. (2009) Evaluation of Injectable Sustained Release Progestin Formulations for Suppression of Estrus and Ovulation in Mares. Journal of Equine Veterinary Science, 29, 33–36. *