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N-acetyl-cysteine (NAC)

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What is N-acetyl-L-cysteine?

N-acetylcysteine (NAC) is a stable precursor to the amino acid L-cysteine.  It is one of only two amino acids that contain sulphur, an element which is essential for health, playing a key role in aspects of metabolism and liver function, as well as the anti-oxidant defense systems of the body and therefore aging.  People living in Iceland have remarkably low rates of some common diseases including diabetes, depression, obesity and heart disease.  There is a significant amount of research which indicates that this may be a result of the high levels of sulphur in the soil and groundwater due to the volcanoes in the area.

NAC & glutathione, the master antioxidant and detoxifier

N-acetyl cysteine is also required for the production of glutathione, which is sometimes called the master antioxidant as it is so potent and also has the ability to recycle other antioxidants in the body such as vitamins C and E.  Women with PCOS generally are under greater oxidative stress than those without it.  Without glutathione, we cannot live.  Glutathione regulates the nitric oxide cycle, which is generally disoredered in PCOS.  It is a part of metabolic and biochemical reactions including making and repairing DNA, protein and prostaglandins, transporting amino acids and activating enzymes.  As a result, every system in the body is influenced by glutathione status, from the immune system to the lungs, the nervous system and the gastrointestinal system.  Glutathione is most plentiful in healthy young people and gradually declines with age.  Studies have found that it is lowest in people suffering from chronic illnesses such as ischaemic heart disease, diabetes, preeclampsia, cataracts, chronic renal failure and leukaemia.  Scientists have hypothesized, based on these findings, that oxidative stress may therefore play a large role in the development of chronic diseases and that antioxidants may provide a potential preventative therapy for them or even a therapeutic role in the treatment of established disease.

Other ways to boost glutathione

Glutathione is naturally produced in the body and exercise increases the rate at which it is produced.  Alpha lipoic acid has also been found to restore levels of glutathione within cells.  Melatonin stimulates a related enzyme called glutathione peroxidase which protects the body from oxidative damage by reducing hydrogen peroxide to water and lipid hydroperoxides to their corresponding alcohols.  The herb St Mary’s Thistle, or more specifically the liver-protective compound contained within it, silymarin, has also been found to replenish glutathione levels in laboratory animal experiments.

All of these things have been found to be beneficial for PCOS.

Other uses for NAC: liver protection, heart disease, HIV/AIDS, cataracts & macular degeneration, Sjogren’s syndrome, myoclonus epilepsy, influenza and hepatitis C

NAC is used in hospitals to treat patients who have overdosed on paracetamol/acetominophen.  It binds to a metabolite of paracetamol, which would otherwise react with cellular proteins, killing the cells in the process, eventually causing the person’s death when too much liver damage has ocurred.  N-acetylcysteine is also used to break up mucus in people with cystic fibrosis and other chronic respiratory diseases or in smokers with lung disease.  It has also begun to be used to increase the survival rate of patients with HIV/AIDS, most likely by enhancing the function of components of the immune system like T-cells, B-cells and phagocytes, by improving glutathione synthesis.  As glutathione is such a potent antioxidant, NAC has been studied in clinical trials for its potential to reduce damage from free radicals which can damage the blood vessels, leading to heart disease, damage the lens of the eye leading to cataracts or the macula, a part of the retina of the eye, leading to macular degeneration.

NAC may also play a role in protecting the liver from heavy metal poisoning from metals including gold, silver, copper, mercury, lead, and arsenic as well as from chemicals including carbon tetrachloride, acrylonitriles, halothane, paraquat, acetaldehyde, coumarin, and interferon, though more research is needed to further investigate the value N-acetylcysteine may offer in cases of poisoning.

Clinical studies have also demonstrated the therapeutic benefit of NAC in the treatment of Sjogren’s syndrome, myoclonus epilepsy, influenza and hepatitis C.

NAC & PCOS

NAC offers a number of benefits to women with PCOS with studies showing a beneficial effect at dosages ranging between 1200 mg and 1800 mg per day.  It has also been found to exert a beneficial effect in the treatment of diabetes, by improving insulin sensitivity.  It lowers TNF-a, suppresses MMP-2 and MMP-9 and inhibits VEGF.  It is a potent antioxidant and increases glutathione synthesis, as discussed above.   In particular, it increases insulin sensitivity, reduces testosterone levels, improves ovulation rates at least in conjunction with Clomid, but probably not as well as metformin does and it lowers homocysteine levels which are usually elevated in women with PCOS.  So far, there have not been adequate studies of the effect NAC may have during pregnancy.

Some studies have found NAC to be comparable to metformin in the treatment of PCOS, but without any of the side effects.

“Results: Both treatments resulted in a significant decrease in body mass index, hirsutism score, fasting insulin, HOMA index, free testosterone and menstrual irregularity compared with baseline values, and both treatments had equal efficacy. NAC led to a significant decrease in both total cholesterol and low-density lipoprotein levels, whereas metformin only led to a decrease in total cholesterol level. Although TNF-? levels increased following treatment for both groups, the difference from baseline was not significant.
Conclusions: Metformin and NAC appear to have comparable effects on hyperandrogenism, hyperinsulinaemia and menstrual irregularity in women with PCOS. The effects of metformin and NAC on insulin sensitivity are not associated with TNF-a.”

Oner et al 2011

Weight loss

In 2011, Oner et al found that 600 mg of NAC, three times per day significantly reduced the body mass index (BMI) in women with PCOS over a 24 week period

Improved cholesterol balance

The researchers reported that NAC at this dose was equally as effective as metformin in treating PCOS, with some additional benefits not seen in metformin treatment, such as an improvement in homocysteine levels rather than the worsening caused by metformin, and a significant decrease in LDL or ‘bad’ cholesterol, whereas metformin only decreased total cholesterol without improving the LDL:HDL ratio.

Lowered testosterone levels, free androgen index and hirsutism scores

Oner et al also reported that testosterone levels and free androgen index were reduced which also resulted in lower hirsutism scores in the women.

Antioxidant activity

PCOS is associated with increased oxidative stress.  NAC, as a precursor to glutathione, is a potent antioxidant which can help to combat this increased oxidation.  It may also reduce the oxidative stress caused by PCOS by improving biochemical parameters such as insulin, glucose and testosterone levels.

Increasing insulin sensitivity

The key driver behind the cascade of metabolic abnormalities we call polycystic ovarian syndrome, in the majority if not all cases of PCOS, is insulin resistance.  N-acetylcysteine was found to improve peripheral insulin sensitivity in women with PCOS who had an impaired response to glucose, in a 2002 study led by Fulghesu et al.  It did not improve sensitivity to insulin in subjects who already had a normal response to insulin, but it did reduce circulating insulin levels, testosterone and free androgen index values in those who did have impaired insulin sensitivity.

“Insulin [area under curve] after [oral glucose tolerance test] was significantly reduced, and the peripheral insulin sensitivity increased after NAC administration, whereas the hepatic insulin extraction was unaffected. The NAC treatment induced a significant fall in T levels and in free androgen index values. In analyzing patients according to their insulinemic response to [oral glucose tolerance test], normoinsulinemic subjects and placebo-treated patients did not show any modification of the above parameters, whereas a significant improvement was observed in hyperinsulinemic subjects. CONCLUSION(S): NAC may be a new treatment for the improvement of insulin circulating levels and insulin sensitivity in hyperinsulinemic patients with polycystic ovary syndrome.”  

Kilic-Okman et all, 2004

Improving fertility outcomes
NAC improves menstrual regularity and ovulation

Oner et all (2011) found that menstrual irregularity was improved in women taking 1800 mg of NAC per day.

NAC improves response to Clomid in women who are resistant

N-acetyl cysteine has shown significant promise for improving the fertility of women with PCOS, in particular those who are Clomid-resistant.  A 2007 study of 5723 women with PCOS by Badawy et al found that adding 600 mg of NAC twice a day in combination with 50 mg of clomiphene citrate (Clomid) resulted in ovulation in 52% of women with PCOS who were Clomid-resistant as opposed to only 18% when they received just Clomid alone.  The women also had an average of 3 mature follicles when taking NAC as opposed to only 2 mature follicles when they were taking just Clomid.  The researchers concluded ”N-Acetyl cysteine is proved effective in inducing or augmenting ovulation in polycystic ovary patients.”

A 2005 study by Rizk et al also found that in 150 women with PCOS who were Clomid-resistant 49.3% ovulated when taking NAC and 1.3% became pregnant.  The study was placebo-controlled, and 21% of the placebo group ovulated with no pregnancies resulting.

Metformin & Clomid seem to work better

A 2010 study by Abu et al concluded that “The efficacy of metformin-CC (clomiphene citrate) combination therapy is higher than that of NAC-CC for inducing ovulation and achieving pregnancy among CC-resistant PCOS patients.”  The study of 193 Clomid-resistant women with PCOS found that over the 3-month study, women who received clomiphene citrate and metformin had three and a half times the rate of ovulation (69% vs 20%) and four times the number of pregnancies (23% vs. 5.3%) when compared with the group who took NAC and clomiphene.  The metformin and CC group also had a lower rate of miscarriage, better luteal phase progesterone levels, oestrogen levels and endometrial thickness than women taking NAC and CC.

NAC may not improve ovulation by itself

Another study by Badawy in 2007, however, found that when comparing NAC against metformin in a small study of 61 women who served as their own controls during the study, it did not offer a significant improvement in ovulation rate or fasting insulin or glucose levels, though it did reduce testosterone levels.  Only 2/30 or 6.7% of women taking 1.8 grams of NAC daily ovulated, compared to 16/31 or 51.6% of women taking 1500 mg of metformin daily.  

Reducing elevated homocysteine levels

Metformin is considered currently to be the gold-standard in pharmaceutical treatment of PCOS, however, it has some very unfortunate side-effects.  It increases homocysteine levels, in addition to causing the well-known gastro-intestinal side effects in most people and potentially causing kidney and liver damage.  Women with PCOS generally tend to have elevated homocysteine levels to begin with, so this is not a good thing.  Elevated homocysteine levels have been strongly linked to an increased risk of cardiovascular disease incuding coronary artery disease and heart attack as well as cervical cancer, cognitive impairment, fibromyalgia and chronic fatigue.

NAC has been studied extensively for its ability to quickly and significantly reduce homocysteine levels in both healthy humans and those with elevated homocysteine levels due to various disease processes.

How to take N-acetylcysteine for PCOS

Amino acids, such as NAC, are best taken on an empty stomach with a full glass of water, an hour before meals.  If amino acids are taken in conjunction with foods containing protein, then they have to compete for absorption with all the other amino acids which make up the protein chains in the food.  Beneficial effects on PCOS may be observed with as little as 600 mg per day, or may require 1200 mg or 1800 mg per day.  Obese women with PCOS were found in one study not to respond to the 1800 mg per day dose, but did show improvement at 3000 mg per day.

A word of caution

NAC may increase urinary zinc excretion, however, the amount of zinc in most multivitamins should be sufficient to protect against NAC-induced zinc deficiency at normal therapeutic doses.

A molybdenum deficiency, which is very rare, can cause an accumulation of sulfite from the catabolism of L-cysteine.  Again, the amount of molybdenum present in either a multivitamin or a healthy, varied diet, should be sufficient to protect against this.

 ***

This article is still a work in progress.  From this point onwards has not been edited but is included for your information anyway.

 

 

N-acetylcysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome

Salehpour S, Akbari Sene A, Saharkhiz N, Sohrabi MR, Moghimian F.
IVF Center, Infertility and Reproductive Health Research Center, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Abstract
The aim of this study was to evaluate the effect of oral N-acetylcysteine (NAC) administration as an adjuvant to clomiphene citrate (CC) on induction of ovulation outcomes in patients with polycystic ovary syndrome (PCOS). In this placebo-controlled double-blind randomized clinical trial, 180 PCOS infertile patients were randomly divided into two groups for induction of ovulation. Patients in group 1 received CC 100 mg/d plus NAC 1.2 g/d and patients in group 2 received CC plus placebo for 5 days starting at day 3 of the cycle. On the 12th day of the menstrual cycle in the presence of at least one follicle with an 18-20-mm diameter in ultrasound evaluation, 10000 U hCG was injected intramuscularly and timed intercourse was advised 36 h after hCG injection. Serum ?-hCG level was measured on the 16th day after hCG injection.
Results: The number of follicles >18 mm and the mean endometrial thickness on the day of hCG administration were significantly higher among the CC+NAC group (P-value = 0.001). The ovulation and pregnancy rates were also significantly higher in the CC+NAC group (P-value = 0.02 and 0.04, respectively). No adverse side effects and no cases of ovarian hyperstimulation syndrome were observed in the group receiving NAC.
Conclusion: NAC as a safe and well-tolerated adjuvant to CC for induction of ovulation can improve the ovulation and pregnancy rates in PCOS patients. It may also have some beneficial impacts on endometrial thickness.

Groups Ovulation Rate Pregnancy Rate
Group I
NAC + 100 mg CC
49.3% 21.3%
Group II
Placebo + 100 mg CC
1.3% 0%

Effect of N-acetyl-cysteine after ovarian drilling in clomiphene citrate-resistant PCOS women: a pilot study

Nasr A.
Women’s Health Center, Department of Obstetrics and Gynecology, Faculty of Medicine, Assiut
University, P.O. Box 1, 71516 Assiut, Egypt. a_nasr02@lycos.com

Abstract
The aim of this randomized double-blind placebo-controlled pilot study was to evaluate N-acetyl-cysteine (NAC) as an adjunctive therapy following unilateral laparoscopic ovarian drilling (LOD) for clomiphene citrate-resistant women with polycystic ovary syndrome (PCOS). A total of 60 patients with clomiphene citrate-resistant PCOS who underwent unilateral LOD were assigned randomly to receive either NAC 1.2 g/d (group A=30) or placebo (group B=30) for 5 days starting at day 3 of the cycle for 12 consecutive cycles. The primary outcome was pregnancy rate; secondary outcomes were ovulation rates, endometrial thickness and pregnancy outcome. Baseline clinical, endocrine, and sonographic characteristics were similar in the two groups. A significant increase in both ovulation and pregnancy rates was observed in the NAC group, compared with placebo [87% versus 67% and 77% versus 57%, respectively, P<0.01]. Moreover, miscarriage rates were significantly lower and live birth rates were significantly higher in the NAC group [8.7% versus 23.5% and 67% versus 40% respectively, P<0.01]. In conclusion, NAC is a novel adjuvant therapy after unilateral LOD which might help improve overall reproductive outcome.

Objective

To evaluate the clinical, endocrine and metabolic effects of metformin and N-acetyl-cysteine (NAC) in patients with polycystic ovary syndrome (PCOS).

Study design

In this prospective trial, 100 women with PCOS were randomly divided to receive metformin (500mg p.o. three times daily) or NAC (600mg p.o. three times daily) for 24 weeks. Hyperandrogenism, lipid profiles, hirsutism scores, menstrual irregularity, insulin sensitivity and tumour necrosis factor-? (TNF-?) levels were measured at baseline and after the treatment period.

Results

Both treatments resulted in a significant decrease in body mass index, hirsutism score, fasting insulin, HOMA index, free testosterone and menstrual irregularity compared with baseline values, and both treatments had equal efficacy. NAC led to a significant decrease in both total cholesterol and low-density lipoprotein levels, whereas metformin only led to a decrease in total cholesterol level. Although TNF-? levels increased following treatment for both groups, the difference from baseline was not significant.

Conclusions

Metformin and NAC appear to have comparable effects on hyperandrogenism, hyperinsulinaemia and menstrual irregularity in women with PCOS. The effects of metformin and NAC on insulin sensitivity are not associated with TNF-?.

 

Abstract

Aim:? The aim of this study was to evaluate the effect of oral N-acetylcysteine (NAC) administration as an adjuvant to clomiphene citrate (CC) on induction of ovulation outcomes in patients with polycystic ovary syndrome (PCOS).

Material and Methods:? In this placebo-controlled double-blind randomized clinical trial, 180 PCOS infertile patients were randomly divided into two groups for induction of ovulation. Patients in group 1 received CC 100 mg/d plus NAC 1.2 g/d and patients in group 2 received CC plus placebo for 5 days starting at day 3 of the cycle. On the 12th day of the menstrual cycle in the presence of at least one follicle with an 18–20-mm diameter in ultrasound evaluation, 10 000 U hCG was injected intramuscularly and timed intercourse was advised 36 h after hCG injection. Serum ?-hCG level was measured on the 16th day after hCG injection.

Results:? The number of follicles >18 mm and the mean endometrial thickness on the day of hCG administration were significantly higher among the CC+NAC group (P-value = 0.001). The ovulation and pregnancy rates were also significantly higher in the CC+NAC group (P-value = 0.02 and 0.04, respectively). No adverse side-effects and no cases of ovarian hyperstimulation syndrome were observed in the group receiving NAC.

Conclusion:? NAC as a safe and well-tolerated adjuvant to CC for induction of ovulation can improve the ovulation and pregnancy rates in PCOS patients. It may also have some beneficial impacts on endometrial thickness.

More Information:

Abu Hashim H, Anwar K, & El-Fatah RA. (2010) N-acetyl cysteine plus clomiphene citrate versus metformin and clomiphene citrate in treatment of clomiphene-resistant polycystic ovary syndrome: a randomized controlled trial. Journal of women’s health (2002), 19(11), 2043-8. PMID: 20939675

Badawy A, State O, & Abdelgawad S. (2007) N-Acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: a cross-over trial. Acta obstetricia et gynecologica Scandinavica, 86(2), 218-22. PMID: 17364286

Badawy A, State O, El Gawad SSh, & El Aziz OA. (2007) Plasma homocysteine and polycystic ovary syndrome: the missed link. European journal of obstetrics, gynecology, and reproductive biology, 131(1), 68-72. PMID: 17123696

Elnashar A, Fahmy M, Mansour A, & Ibrahim K. (2007) N-acetyl cysteine vs. metformin in treatment of clomiphene citrate-resistant polycystic ovary syndrome: a prospective randomized controlled study. Fertility and sterility, 88(2), 406-9. PMID: 17335818

Badawy A, Baker El Nashar A, & El Totongy M. (2006) Clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for augmenting ovulation in the management of unexplained infertility: a randomized double-blind controlled trial. Fertility and sterility, 86(3), 647-50. PMID: 16831439

Fulghesu AM, Ciampelli M, Muzj G, Belosi C, Selvaggi L, Ayala GF, & Lanzone A. (2002)N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome. Fertility and sterility, 77(6), 1128-35. PMID: 12057717

Kilic-Okman T, & Kucuk M. (2004) N-acetyl-cysteine treatment for polycystic ovary syndrome. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics, 85(3), 296-7. PMID: 15145276

Nuttall SL, Martin U, Sinclair AJ, & Kendall MJ. (1998) Glutathione: in sickness and in health. Lancet, 351(9103), 645-6. PMID: 9500325

Oner G, & Muderris II. (2011) Clinical, endocrine and metabolic effects of metformin vs N-acetyl-cysteine in women with polycystic ovary syndrome. European journal of obstetrics, gynecology, and reproductive biology, 159(1), 127-31. PMID: 21831508

Rizk AY, Bedaiwy MA, & Al-Inany HG. (2005) N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate-resistant patients with polycystic ovary syndrome. Fertility and sterility, 83(2), 367-70. PMID: 15705376

Roes EM, Raijmakers MT, Peters WH, & Steegers EA. (2002) Effects of oral N-acetylcysteine on plasma homocysteine and whole blood glutathione levels in healthy, non-pregnant women. Clinical chemistry and laboratory medicine : CCLM / FESCC, 40(5), 496-8. PMID: 12113295

Salehpour S, Sene AA, Saharkhiz N, Sohrabi MR, & Moghimian F. (2012) N-Acetylcysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome. The journal of obstetrics and gynaecology research, 38(9), 1182-6. PMID: 22540635

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