Clomid (Clomiphene) is a medication that hit the market in the 1960s for the treatment of oligomenorrhea (light or infrequent menstrual periods). After its approval, medical practitioners discovered that utilization of Clomid for oligomenorrhea increased odds of fertility, principally via induction of ovulation. This finding spurred an investigation of Clomid as a potential treatment for infertility, for which it was found highly effective.
To this day Clomid remains the most popular medication for the reversal of anovulation. Chemically, Clomid it is comprised of two isomers enclomiphene and zuclomiphene, each of which contribute to its mechanism as a selective estrogen receptor modulator (SERM). Specifically, these isomers bind to estrogenic receptor sites as competitive antagonists, thereby inhibiting negative feedback of estrogen on gonadotropin release.
This yields increased activation of the HPG (hypothalamic-pituitary-gonadal) axis, ultimately stimulating the release of FSH (follicle stimulating hormone) and LH (luteinizing hormone) to induce ovulation. Despite its high efficacy for the induction of ovulation, some users report adverse effects such as: abnormal bleeding, enlarged ovaries, headaches, vision changes – and may be worried about studies that link Clomid to increased risk of ovarian cancer. For this reason, users may discontinue the medication, but wonder how long Clomid stays in their system.
How long does Clomid stay in your system?
If you’ve recently discontinued Clomid, there’s a chance that you may experience lingering side effects for days (or possibly weeks) after your last dose. These lingering side effects may lead you to suspect that Clomid and/or its metabolites may still be in your system and wonder how long before it is fully eliminated. To determine how long Clomid is likely to stay in your system, it is necessary to consider its elimination half-life of 5 to 7 days.
This 5 to 7 day elimination half-life implies that it may take nearly up to a full week after your final dose to eliminate 50% of a Clomid dose from systemic circulation. Knowing that Clomid has such a prolonged elimination half-life, you may be correct in your speculation that it is still in your system – even if it’s been weeks since your last dose. On average, it’ll take between 27.5 and 38.5 days to completely eliminate Clomid from your system; approximately 4 to 6 weeks.
Other reports document that Clomid’s half-life is approximately 2 weeks (14 days), which implies that Clomid may stay in your system for up to 11 weeks after your last dose. Most users should expect Clomid to remain in systemic circulation between 1 and 3 months after their final dose. It should be noted that Clomid is comprised of multiple isomers: enclomiphene (~62%) and zuclomiphene (~38%).
The elimination half-life of the enclomiphene isomer is estimated at 24 hours, whereas that of the zuclomiphene isomer is substantially longer. The enclomiphene constituent is eliminated in less than 1 week, whereas the zuclomiphene constituent is responsible for the protracted term of Clomid’s elimination. Zuclomiphene appears in the plasma well after 1 month of Clomid discontinuation and trace amounts have been reported in fecal excretion after 6 weeks.
- Source: https://pubchem.ncbi.nlm.nih.gov/compound/clomiphene
- Source: http://www.ncbi.nlm.nih.gov/pubmed/3091405
- Source: http://www.ncbi.nlm.nih.gov/pubmed/17697488
- Source: http://www.ncbi.nlm.nih.gov/pubmed/3011587
Variables that influence how long Clomid stays in your system
Although Clomid remains in systemic circulation for an average of 4 to 11 weeks after a user’s final dose, not all users will eliminate the drug at the same pace. Some users may eliminate enclomiphene and zuclomiphene isomers faster than average (in less than 6 weeks), while others may still have zuclomiphene in plasma circulation after 6 weeks. Interindividual differences in elimination speed of Clomid can be explained by variables such as: individual factors, dosage, and term of administration.
Two women may simultaneously ingest 50 mg Clomid for 5 consecutive days early in their menstruation cycle, yet one user may eliminate the drug quicker than the other. In this example, the two women had taken the same dosage of Clomid at the same times and for the same duration. So how is it possible that one user would eliminate its metabolites faster than the other? In this case, differences in elimination speed can be explained by individual factors such as: age, body mass, genetics, and hepatic function.
Body mass + Fat (%): It is known that Clomid is extensively bound to plasma proteins and has a propensity to accumulate in fatty tissues throughout the body. As a result, it is likely that distribution of Clomid and its metabolites may differ between those with low and high BMIs and body fat percentages. Specifically, it is thought that obese women with a high body fat percentage may accumulate greater levels of Clomid not only because they carry more fatty tissue, but because they are likely to be taking higher doses.
Obese women require higher Clomid dosages to induce ovulation because androgen levels are greater than non-obese women. The combination of high dosing along with a greater amount of fatty tissue for accumulation may prolong Clomid’s elimination half-life – especially if taken for a long-term. If you have a high percentage of body fat, and as a result require a supratherapeutic dose of Clomid, expect it to stay in your system for a longer duration after discontinuation.
- Source: https://books.google.com/books?id=vm2eiwmSkAUC
Genetics: Medical literature suggests that Clomid undergoes extensive hepatic metabolism. Although the exact hepatic pathways responsible for its metabolism aren’t fully elucidated, one pathway believed to play a major role is that of CYP2D6 (cytochrome P450 2D6). Since the CYP2D6 gene is considered highly polymorphic, a small percentage of users (3-10%) may carry non-functional CYP2D6 alleles, resulting in poor Clomid metabolism.
Poor CYP2D6 metabolism may fail to yield metabolites necessary to induce ovulation, and plasma concentrations of clomiphene may accumulate, leading to a prolonged elimination half-life. On the other hand, users considered ultrarapid CYP2D6 metabolizers carry multiple functional CYP2D6 alleles, resulting in faster metabolism of clomiphene and increased concentrations of metabolites to induce ovulation. Ultrarapid CYP2D6 metabolizers may eliminate Clomid from systemic circulation at a quicker pace than average.
A majority of Clomid users (~70%) will be considered “extensive metabolizers” in that they carry at least one functional CYP2D6 allele. In this case, the drug should be metabolized at a normative pace and eliminated in an average amount of time. To determine whether you’re a poor, extensive, or perhaps ultrarapid metabolizer of Clomid, you may want to consider a testing service such as GeneSight.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/22108178
Hepatic function: Clomid usage among those with hepatic impairment is medically contraindicated and should be avoided. In the event that someone with hepatic impairment happens to take Clomid, it is possible that plasma concentrations of clomiphene may appear abnormally high. This is due to the fact that hepatic impairment interferes with the functionality of isoenzymes in the liver (e.g. CYP2D6), thereby resulting in poorer metabolism.
The degree to which an individual is hepatically impaired will likely be reflective upon clomiphene’s elimination half-life. Someone with severe hepatic impairment is likely to retain clomiphene isomers (and their metabolites) for a considerably longer duration than someone with normative heaptic function. On the other hand, an individual with mild hepatic impairment may retain clomiphene for slightly longer than usual.
Elimination half-lives of other SERMs (selective estrogen receptor modulators) appear to double when administered to those with hepatic impairment. If similar effects were discovered with Clomid, it would likely remain in a user’s system for 8 to 22 weeks after discontinuation. The greater the severity of a user’s hepatic dysfunction, the longer it’ll likely take to eliminate Clomid from the plasma.
Metabolic rate: An individual’s BMR (basal metabolic rate) may affect how long Clomid is likely to remain in systemic circulation upon discontinuation. Users with a high BMR, characterized by burning more energy (calories) at rest are thought to eliminate exogenous substances at faster rates than those with a low BMR. For this reason, it may be necessary to speculate that if you have a high BMR, you’ll metabolize and excrete Clomid quicker than average.
Basal metabolic rate is also associated with the amount of body fat an individual is likely to carry; a high BMR usually indicates a lower percentage of body fat. As was already mentioned, Clomid has an affinity for fatty tissue and obese users typically require higher doses to induce ovulation. This may suggest that BMR indirectly affects Clomid elimination via influencing a user’s BMI and fat percentage.
Other drugs: Since Clomid is believed to undergo hepatic metabolism via CYP2D6 isoenzymes, it is likely that co-administration of drugs that alter functionality of CYP2D6 may affect its pharmacokinetics. Specifically, any co-ingested agents that inhibit CYP2D6 function will likely prolong elimination of Clomid, whereas agents that induce CYP2D6 function will likely expedite elimination of Clomid. Examples of common CYP2D6 inhibitors include: Bupropion, Cinacalcet, Fluoxetine, Paroxetine, Quinidine, and Ritonavir.
If you happen to be taking a CYP2D6 inhibitor along with Clomid, understand that its metabolism may be compromised – leading to elevated plasma levels and a prolonged term of elimination. Conversely, if you’re taking a CYP2D6 inducer such as: Dexamethasone, Glutethimide, Promethazine, or Rifampicin – expect Clomid to be metabolized at a quicker pace, possibly expediting elimination. Understand that degree of CYP2D6 inhibition/induction from co-administered drugs may vary based on the specific agent administered and its respective dosage.
Renal function: A person’s renal function may have a minor impact on the speed by which Clomid is eliminated from systemic circulation. Though renal pathways don’t play a major role in the excretion of Clomid, they do excrete around 8% of a dose. Therefore, it could be speculated that individuals with varying degrees of renal impairment may fail to excrete this small percentage efficiently.
Renal impairment is known to interfere with efficiency of drug excretion, possibly leading to accumulation and reabsorption in the plasma. While mild forms of renal impairment may not have a noticeable impact on Clomid elimination half-life, severe renal impairment may have a more pronounced effect on excretion. Consider that if you suffer from renal impairment, Clomid may linger in your system for a longer term than someone with normative kidney function.
Sex: Although Clomid is primarily utilized by women to induce ovulation, it is sometimes prescribed as an off-label treatment for hypogonadism among men. Since males may also use Clomid, it should be hypothesized that there could be sex-specific differences in Clomid’s pharmacokinetics. Men may exhibit altered plasma concentrations and/or volumes of distribution compared to women, potentially leading to differences in elimination half-lives.
Daily Dosage (50 mg to 250 mg)
The dosage of Clomid administered is likely to affect how long it remains in your system after discontinuation. If you took a daily dose of just 50 mg, you’d likely eliminate it much quicker than had you taken 250 mg. Consider that discontinuation from 250 mg would leave approximately 125 mg in systemic circulation after 5 to 7 days (the half-life), whereas discontinuation from just 50 mg would leave around 25 mg in systemic circulation.
If you were taking a high dose, a greater amount of the Clomid will linger in your plasma for a longer term than if you were taking a low dose. Furthermore, it is necessary to consider that a high dose will likely place a greater burden on hepatic pathways responsible for Clomid’s metabolism. The greater burden results from the fact that a large quantity of Clomid necessitates hepatic metabolism, but isoenzymes can only metabolize a set quantity of the drug at a time.
Once this threshold quantity is exceeded, efficiency of metabolism is compromised, and it takes longer to break-down Clomid. It should also be considered that once a high dose is metabolized, a greater quantity of enclomiphene and zuclomiphene isomers will enter circulation. The increased amount of clomiphene isomers in circulation may result in heightened isomer accumulation within tissues and possibly increased enterohepatic recirculation.
Additionally, it is possible that higher doses may accumulate in excretion pathways and once levels exceed a specific threshold, efficiency of excretion may be compromised. Therefore, if you are taking a standard dose of 50 mg, Clomid should be metabolized and excreted more efficiently than if you were taking double, triple, or quadruple the amount. With each doubling of dosage, elimination half-life may be extended.
Term of administration + Cycles
Medical instructions dictate that Clomid is to be taken 5 consecutive days, which in turn will likely trigger ovulation within 5 to 9 days thereafter. Some individuals may take Clomid for shorter and/or longer durations than 5 days based on individualized instructions from their doctor. In general, the shorter your term of administration, the quicker you should expect Clomid to be eliminated from systemic circulation.
The longer your term of administration, the greater the duration you should expect Clomid isomers (particularly zuclomiphene) to linger in your system. A prolonged term of administration means that you likely ingested a greater cumulative dose prior to its elimination. Someone taking 50 mg for 4 days will have ingested 200 mg Clomid and will excrete the drug quicker than someone taking 50 mg for 6 days (for a total of 300 mg).
The longer the term over which you administer Clomid, the later the date at which your final dose undergoes metabolism and circulation. This later metabolism, coupled with the greater quantity of ingested Clomid may prolong its elimination compared to a shorter-term user. In addition to term of administration, it may be necessary to consider the number of cycles over which Clomid is taken.
Individuals that have taken Clomid for multiple cycles may be instructed to increase dosages on consecutive cycles. Furthermore, taking Clomid for more than one cycle means that Clomid administered from an initial cycle may still remain in a user’s plasma. Since complete plasma elimination can take up to 3 months, usage of Clomid for several cycles may result in greater accumulation, and ultimately protracted elimination compared to those who’ve taken it for just one or two cycles.
Clomid: Absorption, Metabolism, Excretion (Details)
Following oral administration of Clomid, its active ingredient clomiphene is rapidly absorbed via the gastrointestinal (GI) tract. Clomiphene’s isomers (62%) enclomiphene and (38%) zuclomiphene are subject to hepatic metabolism. Studies suggest that both isomers are likely metabolized via CYP2D6 isoenzymes and yield metabolites such as: (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene.
It is these metabolites that are likely responsible for the majority of estrogenic receptor competitive antagonism. After metabolism of enclomiphene and zuclomiphene, they are extensively bound to plasma proteins and distributed (along with their respective metabolites) and plasma concentrations peak around 6 hours post-ingestion. Clomiphene isomers and metabolites appear to accumulate within fatty tissues and are thought to exhibit a high degree of lipophilicity.
The enclomiphene isomer exhibits an elimination half-life of around ~5 days, whereas that of zuclomiphene is understood to be noticeably longer. The elimination half-life of clomiphene is reportedly between 5 and 14 days. A majority of enclomiphene is eliminated in less than 28 days after discontinuation, whereas zuclomiphene elimination may take up to 77 days.
Differences in isomer elimination may be due to increased propensity of enterohepatic recirculation of zuclomiphene. Zuclomiphene metabolites are commonly detected in fecal samples collected 6 weeks after single-dose administration of Clomid. Fecal excretion accounts for up to 50% of clomiphene elimination, whereas renal excretion accounts for 8%.
- Source: https://pubchem.ncbi.nlm.nih.gov/compound/clomiphene
- Source: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016131s026lbl.pdf
- Source: http://www.ncbi.nlm.nih.gov/pubmed/22108178
- Source: http://www.ncbi.nlm.nih.gov/pubmed/19033451
Tips to clear Clomid from your system
If you’ve been taking Clomid, there may be some steps you can take to ensure that it gets eliminated from your system in a timely manner. That said, should you actively consider taking steps to expedite the elimination of Clomid from systemic circulation, be sure to verify their safety and efficacy with a medical professional. Realize that certain suggestions may provide greater detoxification benefit than others.
- Activated charcoal: An effective supplement to ensure detoxification from various drugs is that of activated charcoal. Activated charcoal binds to unmetabolized substances as well as endotoxins that may have been generated by administration of Clomid. Though activated charcoal is likely not likely going to have a major impact in bolstering Clomid excretion, it may aid in detoxification following treatment.
- Exercise: Due to the fact that Clomid is likely lipophilic and is thought to accumulate in “fatty tissue,” it is possible that exercise may aid in the burning of excess fatty tissue that could harbor clomiphene and its metabolites. Although regular exercise is unlikely to make a major difference in elimination time of Clomid, it could slightly expedite the process. Consider going for a jog or engaging in some sort of cardio to burn excess fat to force Clomid metabolites from storage.
- Calcium-d-glucarate: A very small percentage (~8%) of clomiphene is excreted from the body via the kidneys. Although your kidneys likely don’t need the extra help for such a small percentage of clomiphene, supplementing with calcium-d-glucarate may expedite renal excretion. Calcium-d-glucarate is known to act as a beta-glucuronidase inhibitor, clearing out a build-up of molecules within renal detoxification pathways. This could help eliminate the 8% of renally excreted Clomid at a slightly faster rate.
How long has Clomid stayed in your system after stopping?
If you’ve stopped using Clomid, you may notice that you’re still experiencing unwanted side effects and/or irregular menstrual cycles. This may lead you to suspect that there’s still some Clomid (likely the zuclomiphene isomer) in your system. As a result of the drug’s protracted half-life, some users report a carryover effect in that the effects of Clomid may persist for at least 1 additional cycle beyond that for which it was taken.
Though medical literature doesn’t support this carryover effect, it does suggest that spontaneous ovulatory menses have been noted in some patients after Clomid therapy. Realize that it is possible for Clomid to remain in your system during pregnancy. That said, a majority of the drug should be out of your system within 6 weeks after your last dose.
Only if you were taking high doses should you expect Clomid to remain in circulation at high levels for a protracted duration. If you’ve taken Clomid, be sure to share a comment mentioning how long you think it stayed in your system? To help others understand your situation, mention the dosage you took, number of days / cycles over which you took it, as well as how long you noticed side effects and/or menstrual irregularities upon discontinuation.