Continuing my series of posts on supplements and recovery of mising periods… overview here, and post on Vitex here 🙂 I am going to review acetyl-l-carnitine next as it is a supplement for which there is evidence for effectiveness in restoring missing menstrual periods from controlled clinical studies. Thanks to Addie for helping with the research!
Here’s a table of contents for this post, as it ended up being super long!!
- Research studies on taking ALC for HA recovery:
- Side Effects
- ALC and oral ovulation induction medications (e.g. Glomid, Femara)
- Does ALC cause weight loss that is potentially detrmental to hypothamic amenorrhea recovery
- ALC and pregnancy
Alright, let’s get started. First, acetyl-L-carnitine, also known as L-acetylcarnitine, ALC, or ALCAR, is a derivative of the amino acid L-carnitine (aka levocarnitine). L-carnitine acts as a recipient of an acetyl group in a reaction that releases CoA for use in the Krebs cycle that generates energy (ATP) in the mitochondria. ALC is naturally synthesized in our bodies on an ongoing basis, and crosses the blood/brain barrier, therefore potentially affecting brain hormones, chemistry, or brain function. Studies have been performed examining the effectiveness of ALC in a number of indications, ranging from diabetic neuropathy to Alzheimer’s disease.
Chemical structure of Acetyl-L-Carnitine:
There isn’t a huge amount of information about the mechanism by which ALC could potentially affect these different diseases, although there are studies that show that ALC upregulates various transporter proteins and transcription factors that could play a part in how it is working. One interesting study in rats showed that ALC induces dopamine release – which may play a part in its effectiveness in restoring missing periods and hypothalamic amenorrhea (HA) recovery.
ALC and Hypothalamic amenorrhea
We cover ALC as a supplement to potentially help with period restoration in our book/ebook No Period. Now What? in Chapter 17, “Still No Period?” along with a number of other suggestions. In this post we will dive much more deeply into the two studies that have been performed using ALC in women with HA, and discuss the results of a third (I can’t get the full text right now because the article is too recent and not available to me electronically yet).
It is important to note that all three studies were performed by the same group so there is not independent confirmation of the effectiveness of ALC, although I can certainly share some anecdotes from women who have used it after examining this evidence (in another post ’cause this one is already a monster!!).
The first study was performed in 1991, on 20 women with amenorrhea. The criteria for participation were:
- amenorrhea for 6+ months and not pregnant
- normal development
- no markers of metabolic disease
- weight stable for the last 12 months (noted that subjects were 5-9% below “ideal weight”)
- normal adrenal and thyroid hormones
Patients were divided into two groups – 10 patients with LH less than 3 IU/mL (average of 0.9 +/- 0.1) and 10 with LH greater than 3 IU/mL (average of 7.1 +/- 1.5). Unfortunately no control group, but I guess we assume each person is their own control and with 6+ months of amenorrhea likelihood of natural cycles returning without any change in habits is low.
The researchers did some pretty cool endocrine testing – looking at GnRH pulsatility at the start of the study and after six months of taking 2g/day of ALC, a GnRH test to look at LH and FSH response to GnRH, and a TRH test (I have no idea what that is). Women who got a period were evaluated at CD8-10.
In this study, 6/10 of the women in the low LH group menstruated after taking ALC for between 3 and 6 months, and 4/10 of the women with normal LH. LH levels in the first group increased from an average of 0.9 to 3.5 IU/mL. LH levels in the second group also increased a bit, but the result was not reported as it was not statistically significant.
Of great interest to me is that in the low LH group, the LH response to GnRH challenge was about 3-fold higher after six months of ALC, and the amount of LH secreted with each pulse was more than 4-fold higher. In the high LH group LH response to GnRH challenge was a bit higher, but not statistically significant.
This is an extremely promising result because the ALC seems to be getting at the underlying cause of hypothalamic amenorrhea – insufficient GnRH pulses from the hypothalamus. After six months of treatment, those with low LH had a much more normal hormonal profile, and 6/10 had restored menstrual cycles.
There ARE some caveats to this. There is no mention of any control over eating or exercise, no mention of weight change, or psychological changes… basically no examination of any other factors that could potentially be causing the increased hormonal response separate from ALC. However, given that ALC is a substance our bodies make naturally, and there do not seem to be adverse side effects from ALC, I feel comfortable recommending this as a supplement to take while working to regain missing periods.
As I said, the second study was performed in 2011 by the same group, but with some improvements (IMHO). First of all, they report asking the women not to make any lifestyle changes during the course of the study. While one cannot guarantee this request was followed, at least an attempt was made. Second, they were more specific in their recruitment criteria. In addition to the criteria from the first study,
- they did not include women with a BMI < 19 (they were trying to assess stress-induced amenorrhea)
- subjects reported a history of emotionally stressful events prior to period cessation
- weight loss within the last 6-12 months (this one seems odd to me if they were trying to get at stree-induced amenorrhea alone, unless they are counting weight loss as a stressor which I don’t necessarily agree with)
- no evidence of hyperandrogenism or polycystic ovaries.
Subjects were divided by LH level similar to the first study, this time with 16 patients in the low LH group and 8 in the higher LH group.
Another difference is that in this study women took 1g ALC per day as opposed to 2g, and for only 16 weeks.
The hormonal tests were also somewhat different – LH pulses were measured again, but this time response to naloxone was measured. This is a drug that prevents binding of natural molecules like B-endorphins to opioid receptors, effectively blocking activation of the receptors leading to increased GnRH secretion and a resultant increase in LH. A number of other hormones were measured before and after treatment – LH, FSH, PRL, estradiol (E2), androstenedione (A), 17-hydroxy-progesterone (17OHP), TSH, free T3 (fT3), free T4 (fT4), insulin, C-peptide, cortisol and testosterone (T).
The overall result was that 10/16 of the low LH subjects had at least one period during the 16-week treatment phase, and 3/8 of the normal LH subjects.
In this case, BMI was reported and the average BMI did increase – by 0.8 BMI units in the low LH group and 0.3 units in the normal LH group. This was not statistically significant, but if the gain was from extra energy intake, could confound the results to some degree. (i.e. ALC without weight gain may not be as effective.)
The hormonal results were again extremely interesting. As in the prior study, LH increased significantly in the low-LH group, from 1.4+/-0.3 IU/mL to 3.1+/-0.4 IU/mL after treatment. In the normal LH group, the increase was from 4.2 to 5.9 IU/mL, still nothing to sneeze at (although not significant statistically.) Increases in estrogen were also seen (similar to the first study) from 29.9 to 40.8 in the low LH group and 37.4 to 52 in the normal LH group.
The response to the naloxone test was even more surprising. Neither group responded to naloxone when given prior to ALC administration, however, the low LH group responded nicely with an increase in LH (normal response) after the 16 weeks (with a three-fold higher max LH pulse and overall 8-fold increase in amount of LH secreted). The normal LH group did not show a response at either timepoint, suggesting a different neurochemical cause for their hypothalamic amenorrhea.
As far as the most important outcome of period recovery, unfortunately all we are told is that 10/16 women in the low LH group and 3/8 in the normal LH group had at least one period. I would have love to see a table with information about the individual participants, an idea of WHEN during the 16 weeks the periods occurred, if they continued again afterward…
This third study was similar in recruiting 27 women with HA, and dividing them into low- and normal-LH groups. In this case the subjects took 250mg ALC and 500mg L-carnitine per day. Again, LH levels increased, mostly in the low LH group. The new findings in this study were that cortisol and amylase levels were decreased in women with low LH, which would lead to a release of repression of the hypothalamus. In addition, the 17-OH-progesterone (17-hydroxy-progesterone) to cortisol ratio increased, which the authors state shows a reduction in stress-induced adrenal activity.
The three studies together certainly build a good case for taking ALC, but I really wish that another research group would attempt to repeat the results.
Toxnet says that side effects may include: “Transient nausea, vomiting, abdominal cramps,
diarrhea, body odor. “(interesting!!) One member of my FB group mentioned that the ALC made her really itchy!
Toxnet continues, “Levocarnitine may cause seizures in patients with or without pre-existing seizure disorder. Headache, dizziness, and transient visual blurring have been reported in patients taking high doses of levocarnitine. ” (Note that this is for L-carnitine, not ALC)
I was curious about the mention of seizures because they did not include any abstracts for papers referencing seizures and came across this review, that found no evidence in the medical literature for ALC-induced seizures. Therefore unless you already have a seizure disorder, I do not believe this is a legitimate concern.
Acetyl-l-carnitine and ovulation induction drugs
As I was discussing this post in my Facebook group, the question came up of whether one could or should take ALC at the same time as ovulation induction oral medications like Clomid or Femara. This gets into much more theoretical territory. There are a few studies looking at response in women with PCOS, and one in women with unexplained infertility – neither necessarily strongly related to women with or recovered from hypothalamic amenorrhea.
The first study looked at ALC and Clomid in women with PCOS who did not respond to Clomid alone. The results were actually quite remarkable – 64% of women taking ALC+Clomid ovulated versus 17% of those taking Clomid alone, the number of mature follicles was an average of 2.2 in the ALC+C group versus 0.16 in the Clomid only group, fewer days were needed for follicular maturation, uterine lining was thicker by more than 3mm (that is HUGE, especially given the propensity of Clomid to thin the lining!!), progesterone during the luteal phase was 30% higher, and the pregnancy rate was 49% with ALC+Clomid versus 1% with Clomid alone. All these differences were statistically significant. Holy smokes Batman! OK, so with HA we have to temper our excitement a little bit because clearly the mechanisms are different from PCOS – but certainly this suggests no detriment to continuing to take ALC along with Clomid. (And there would similarly be no reason not to take it with Femara, the mechanisms of Clomid and Femara are different but neither should involve anything ALC related.)
Here’s another study in PCOS of acetyl-l-cysteine (a different amino acid, but still an acetyl group donor) and Clomid with similar improvements in ovulation rate but not striking differences in the other measured outcomes. And an additional study that found no differences in any fertility related parameters in women with PCOS taking acetyl-l-cysteine + Clomid + letrozole vs Clomid + letrozole alone, but they also supplemented with injected FSH for 4+ days which I think could overwhelm any effect of the cysteine.
Another article looked at acetyl-l-cysteine and Clomid in women with unexplained infertility. The study groups (ALC+ Clomid and Clomid alone) were each about 400 women in size, so a very reasonably powered study. No difference in any ovulation parameters or pregnancy rates was seen.
Overall it seems that there is no detriment to taking ALC along with Clomid or Femara, and there may be a benefit (oh how I wish I had the capacity to run clinical trials!!!). Obviously there is zero evidence that ALC will help the ovulation induction drugs work in the absence of lifestyle changes (eating more/exercising less/stress reduction) as we recommend in our book No Period. Now What? so no recovery shortcuts here 🙂
is ACETYL-L-CARNITINE related WEIGHT LOSS a thing, and detrimental to period recovery?
Various places on the web tout ALC as a weight loss supplement, which is obviously not a desired effect when one is trying to recover missing periods. However, there are zero scientific studies supporting use of ALC in weight loss that I could find. Based on reading some of the websites it seems that their hypothesis is that because ALC is involved in the Krebs cycle in the mitochondria, which gets energy from fatty acids, that means “ALC helps burn fat.” There is not much in the scientific literature on this topic, but I did come across an article that found no difference in metabolic parameters in study participants taking L-carnitine versus controls (not exactly the same things as acetyl-L-carnitine, but they are used somewhat similarly in the body, there just isn’t the extra acetyl group in the L-carnitine). Essentially the only way that ALC could lead to weight loss is if there is not enough around to fully metabolize all the fat and fatty acids that the body needs. This does not seem to be the case. In the second study described above, the participants average BMI increased slightly, and anecdotally, the women in my facebook group who have taken the ALC have not experienced weight loss because of it. So I don’t think this aspect is a concern.
ACETYL-L-Carnitine and pregnancy
If one is taking ALC to restore periods there is a possibility of pregnancy occurring – either before your first period, if you happen to have intercourse before/while you ovulate the first time, or during a subsequent cycle. If this does happen, the recommendation is to stop taking ALC, due to lack of studies on it’s effects during pregnancy. As ALC is synthesized by our own bodies it is unlikely to be harmful and certainly doesn’t warrant any anxiety if you take it before you know you’re pregnant or during the first few weeks, but the long term effects are unknown so one should not take it throughout pregnancy without a strong reason to do so. Toxnet, the database of substance toxicity says, “Precautions: Because of lack of long-term safety studies, ALC is not advised for pregnant women or nursing mothers. Those with seizure disorders should only use ALC under medical advisement and supervision.” Under the section on exposure, the review states, ” A) Levocarcitine is in FDA Pregnancy Category B. Positive correlations between carnitine concentrations in maternal and umbilical venous blood have been reported, suggesting placental transfer. It is not yet known whether levocarnitine is excreted in human milk.
So taking ALC is perhaps not ideal while breastfeeding either.
Acetyl-l-carnitine appears to lead to increases and decreases in hormones as are expected and necessary for recovery of periods missing due to hypothalamic amenorrhea. (e.g. GnRH, LH, estradiol, cortisol…) I think that this is a very reasonble supplement to take as you work toward recovery, assuming you are not taking any medications that interact (please check with your doctor and pharmacist).
It seems like there is a potential for added benefit while taking oral ovulation induction medications like Clomid or Femara; at the very least there is no evidence that it will prevent an ovulation that would otherwise have occurred.
ALC should probably be stopped once a woman is pregnant and not taken until breastfeeding ceases, due to lack of information about pregnancy effects, and a likelhood of being transferred to a baby through breastmilk.
I hope this was helpful!