A meta-analysis concludes that not only does the use of HRT not lead to an increased risk of cancer recurrence in breast cancer survivors but also leads to a significant decrease in mortality from all causes (3% vs 11.4%).

The use of chemotherapy has a cytotoxic effect on the ovaries, resulting in premature ovarian failure in between 20% and 80% of women, which leads to a deficiency in sex hormones. Moreover, the use of antiestrogenic drugs and aromatase inhibitors worsens the hormone deficiency and leads to symptoms that make about 50% of women suspend their tamoxifen treatment.

Dr. Alfonso Galán González – Neolife Medical Team

If there is one thing us doctors should do is to learn, unlearn, and relearn. We are obliged to be aware of the new evidence that scientific literature presents, even if this goes against what we have been previously taught.

In Part 1 of this article, we discussed the relationship between HRT and breast cancer, and the safety of the use of Hormone Replacement Therapy with bioidentical hormones. Now we will ask ourselves what does the literature say about its use in patients who are breast cancer survivors?

It is difficult to find literature in this regard due to different factors. One is, of course, that due to the fear of “causing cancer” with HRT, which we already know is unjustified as mentioned in Part I of this article, there are not many studies available, and much of them have been done on women who, due to the effects of chemotherapy or treatment with estrogen receptor inhibitors, such as tamoxifen, present intolerable symptoms of estrogen deficiency, like hot flashes, above all.

The other factor is, as we also discussed in our previous post, the enormous confusion created by studies when they group under the term “estrogen” the synthetic kind, like conjugated equine estrogens (CEE), and the bioidentical kind (estradiol), and under the term “progestogen” all those drugs with progestogenic effects and which act on progesterone (PR) receptors without distinguishing between progestins (synthetic derivatives) and bioidentical progesterone.

This distinction, which they rarely make, is vital as we have explained in multiple articles, since the effects of synthetic progestins and estrogens are radically different from those compounds that occur naturally in a woman’s body, especially in their link to the development or, in this case, recurrence of cancer.

Breast cancer

Breast cancer accounts for 30% of cancers diagnosed in women in Spain. Its incidence is estimated at 1 in 8 women (13%). The peak of incidence is between the ages of 45 and 65. In the group of women diagnosed later (>50 years), the presence of cancer with positive hormone receptors is much more likely.

It is not the goal of this article to delve into the causes and different classifications or treatments according to stages.

For the purpose of this article, we would like to note that the use of chemotherapy has a cytotoxic effect on the ovaries, resulting in premature ovarian failure in between 20% and 80% of women, which leads to a deficiency in sex hormones. Moreover, the use of antiestrogenic drugs and aromatase inhibitors worsens the hormone deficiency and leads to symptoms that make about 50% of women suspend their tamoxifen treatment.

Therefore, if for the purposes of treatment, we consider the age at which the pathology usually occurs, we find that a large number of women will have a deficiency in sex hormones, either due to menopause or the prescribed treatments.

The deterioration of quality of life associated with this is very important, not only due to physical symptoms like hot flashes, urogenital, or psychological symptoms, it also leads to osteoporosis, cardiovascular disease, and cognitive decline among many other things.

So, what do we do with these women? Do we have to deny them Hormone Replacement Therapy (HRT), that would be so beneficial to them, because they had breast cancer?

Let’s see what the available scientific literature and basic science have to say.

Meurer et al. completed a meta-analysis that concluded that not only does the use of HRT not lead to an increased risk of cancer recurrence in breast cancer survivors but also leads to a significant decrease in mortality from all causes (3% vs 11.4%).

Batur et al. demonstrated similar results with a lower risk of death associated with breast cancer in women using HRT with a 50% reduction in the risk of recurrence.

Randomized clinical trials (RCTs) showed mixed results, with some mentioning a higher, while others a lower risk. The reasons for these differences may be varied (different ages, types of tumors, different follow-up times, etc.) but above all it is the various types HRTs used. Most of them used synthetic estrogens and synthetic derivatives of progesterone, progestins like medroxyprogesterone acetate-MPA, which we already know since the publication of the WHI Study, widely mentioned in these texts, which are associated with breast cancer and thromboembolic disease.

If we delve a little deeper and look at the interventions made in these RCTs and select the studies that used bioidentical hormones, we get very interesting results.

The study conducted by Natrajan et al. using bioidentical estradiol and testosterone in pellets and usually with megestrol as a progestogen, showed that there was no increase in recurrences or mortality associated with breast cancer. The use of bioidentical estradiol and a progestin like megestrol, which the literature tells us does not have an association with cancer like others such as the aforementioned MPA, levonorgestrel or NETA (norethisterone acetate), may be the reason for these good results.

The study conducted by Fahlen et al. and published in the European Journal of Cancer, decided to continue the Stockholm trial that had studied women receiving estradiol and MPA and which was stopped abruptly in light of the results of the HABITS study. The HABITS study was stopped because they observed an increase in breast cancer recurrence in women using HRT consistent with estrogens with NETA or estrogen alone without progestogen opposition. At the moment it was suspended, the Stockholm trial had not shown an increase in recurrences after 4 years of follow-up. Fahlen continued the study until its year 10, lowering the dose of the progestin used, MPA and maintaining oral estradiol. The result? No significant differences were found between the two groups in terms of mortality or recurrence.

Finally, I will mention the study conducted by Le Ray et al. in which they applied local transdermal estradiol in women with symptoms of vaginal dryness associated with their treatment. They did not observe a higher risk of recurrences in any of the groups (treated with tamoxifen, aromatase inhibitors or only local estradiol).

The basic science that studies how hormone receptors behave in normal breast cells and in cancer cells gives us some important clues as to what all these studies mean.

Years of research have revealed a complex and sometimes functionally contradictory connection between estrogen receptors (ER) and progesterone receptors (PR) and breast cancer. There seems to be a clear difference in tissue response to the presence of estradiol and progesterone between normal breast cells and cancer cells. While in healthy tissue, they lead to the proliferation of ER- and PR- milk-producing cells; in cancer cells (much richer in ER+ and PR+ cells), these will be the cells that proliferate in the presence of estrogen with progesterone, thus leading to an antiproliferative effect.

A recurrent observation is that, in breast cancer cases with ER+, PR agonists present a clinical benefit, a conclusion supported by the abundance of clinical data showing the efficacy of progesterone treatment in this disease. By exploiting this interaction between the activation of both receptors, we find a unique opportunity for the treatment of breast cancer with positive hormone receptors. Its use with agents that connect to the ER seems more effective.

When only estrogen receptors (ER) are activated, a stimulus is produced for the transcription of factors that lead to an increase in cell proliferation. While if progesterone receptors are activated at the same time, the genes on which the ER act are reprogrammed, thus increasing the expression of genes, which stops the cell cycle and growth.

The observation that postmenopausal women with PR+ tumors have better prognosis, while postmenopausal women do not, is explained by the presence of an ovary still producing progesterone in the former and not in the latter, who must receive an exogenous progestogen to obtain some clinical benefit.

Therefore, and in conclusion, the available scientific evidence would support the use of HRT with bioidentical hormones in breast cancer survivors as long as this includes the use of progesterone, of course. What about tumors that express hormone receptors (ER + PR+)? The answer may be the same. In fact, the studies I mentioned – and some I have not mentioned – that have shown benefits in recurrence in their results reported including tumors with ER+. It seems more than clear, from the above, that progesterone is not only safe but could be an essential component of the treatment, especially in women with non-tamoxifen-responsive active cancers. Can estradiol be the bond to estrogen receptors that is required for progesterone to exert its anticancer effect? Is all we actually need simply “something” to bond to the ER that is initially an antagonist like tamoxifen or an agonist like estradiol? That would be a very interesting clinical trial and very important for women being treated forbreast cancer with positive receptors, since the difference in their quality of life, after receiving one or the other compound can be very different. What is clear is that we must rethink very seriously the somewhat simplistic idea that ER is activated with estradiol and inhibited with tamoxifen. What happens once “something” bonds with the receptor is much more complex than we thought and may be the answer to explain the different post-cancer evolutions.

BIBLIOGRAPHY

(1) Mudhune GH, Armour M, McBride KA. Safety of menopausal hormone therapy in breast cancer survivors older than fifty at diagnosis: A systematic review and meta-analysis. Breast. 2019;47:43-55. doi:10.1016/j.breast.2019.06.002

(2) O’Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst. 2001;93(10):754-762. doi:10.1093/jnci/93.10.754

(3) Carroll JS, Hickey TE, Tarulli GA, Williams M, Tilley WD. Deciphering the divergent roles of progestogens in breast cancer. Nat Rev Cancer. 2017;17(1):54-64. doi:10.1038/nrc.2016.116

(4) MeurerLN,LenaS.Cancer recurrence and mortality in women using hormone replacement therapy: meta-analysis. J Fam Pract 2002;51:1056e62.

(5) Batur P, et al. Menopausal hormone therapy (HT) in patients with breast cancer. Maturitas 2006;53(2):123e32.

(6) Natrajan PK, Soumakis K, Gambrell JrJr. Estrogen replacement therapy in 
women with previous breast cancer. Am J Obstet Gynecol 1999;181(2):288e95.

(7) Le Ray I, et al. Local estrogen therapy and risk of breast cancer recurrence among hormone-treated patients: a nested case control study. Breast Canc 
Res Treat 2012;135(2):603e9.

(8) Fahlen M, et al. Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial. Eur J Cancer 2013;49(1):52e9.

La entrada Hormone Replacement Therapy and Breast Cancer: Tearing Down Myths through Scientific Evidence. Part II se publicó primero en Neolife.

Progesterone, compared to medroxyprogesterone (MPA), is associated with increased efficacy, patient satisfaction, and quality of life. The procarcinogenic effects of synthetic progestins contrast with the anticancer properties of progesterone.

A terribly common mistake among the general population and, unfortunately, also in the scientific community, is to put bioidentical hormones and synthetic hormones under the same umbrella. The estradiol that women naturally produce is not the same as a synthetic derivative of estradiol or some natural compound like estrogens obtained from a mare. The progesterone that women produce normally until menopause is also not the same as progestins, that is, synthetic derivatives of progesterone.

Dr. Alfonso Galán González – Neolife Medical Team

If there is one thing us doctors should do is to learn, unlearn, and relearn. We are obliged to be aware of the new evidence that scientific literature presents, even if this goes against what we have been previously taught.

In this blog post, we will address an always thorny issue, which we have discussed on other occasions, but which we consider necessary to revisit, and that is the effects of HRT (Hormone Replacement Therapy) on menopause and breast cancer.

We have commented in many other blog posts on the “source” of this stream of “hormone phobia” and fear of the effects of hormones on menopause. The Women’s Health Initiative (WHI) study published in 2002 was hastily suspended when an increase in breast cancer incidence was observed in the studied population, which was being treated with conjugated equine estrogens (CEE) and medroxyprogesterone. This received great media coverage and the issue was magnified, leading to the idea that providing estrogen and progestogens to menopausal women caused breast cancer, which in turn led to thousands and thousands of women abandoning their treatments. This has remained in the back of the minds of all the doctors who were practicing or studying at the time. But if there is one thing us doctors should do is to learn, unlearn, and relearn. We are obliged to be aware of the new evidence that scientific literature presents, even if this goes against what we have been previously taught. Can you imagine practicing for 40 years the same thing we were taught in medical school and our residency?

Estradiol vs estrogens and progesterone vs progestogens and progestins

A terribly common mistake in the general population and, unfortunately, also in the scientific community, is to put bioidentical hormones and synthetic hormones under the same umbrella. The estradiol that women naturally produce is not the same as a synthetic derivative of estradiol or some natural compound like estrogens obtained from a mare. The progesterone that women produce normally until menopause is also not the same as progestins, that is, synthetic derivatives of progesterone.

Bioidentical hormones are molecularly and structurally the same as those produced by a woman’s ovary until menopause, and therefore act on the same receptors and have the same effects. However, synthetic derivatives or hormones obtained from other living organisms such as animals or plants are not; they have estradiol and progesterone-like effects because they are similar enough, and this allows them to bind somewhat to their receptors, but not enough to produce all the effects bioidentical hormones produce. On the contrary, they interact with other receptors and produce metabolites that cause undesired effects.

The studies themselves, when analyzing the results, often do not distinguish between one thing and the other, but they are totally different interventions, as we will see.

What do the studies say?

Starting with the already mentioned WHI study, indeed, the women taking CEE (conjugated equine estrogens) and medroxyprogesterone showed an increased risk of breast cancer; however, the part of the study that only included treatment with CEEs showed a decrease in the risk of breast cancer, making it clear that it is the medroxyprogesterone that causes this excess risk. Many other subsequent studies have confirmed this assessment.

Incidentally, the social alarm caused by this study led to the withdrawal of thousands of treatments. Years later, another famous study published in the American Journal of Public Health estimated that it had caused the premature death of between 18,000 and 90,000 women.

So, what effects do synthetic estrogens, estradiol, progestins, and progesterone have on breast tissue?

Chang et al. examined the effects of applying an estradiol and progesterone gel to women before breast surgery. Estradiol increased cell proliferation by 23%, but progesterone lowered proliferation rates by 400%, thus concluding that when we give progesterone with estradiol, it inhibits estradiol-induced proliferation. All subsequent studies such as the one conducted by Foidart et al. have confirmed this assessment.

Progesterone, compared to medroxyprogesterone (MPA), is associated with increased efficacy, patient satisfaction, and quality of life. More importantly, the molecular differences between synthetic progestins and progesterone result in different effects on breast tissue. The procarcinogenic effects of synthetic progestins contrast with the anticancer properties of progesterone, which results in very different clinical effects on breast cancer risk. Progesterone has an antiproliferative and antiestrogenic effect on both the endometrium and breast tissue, while synthetic progestins have antiproliferative and antiestrogenic effects on endometrial tissue, but have a proliferative effect on breast tissue. Synthetic progestins show increased proliferation of estrogen-induced breast tissue and a risk of breast cancer, while progesterone inhibits breast tissue proliferation and reduces the risk of breast cancer.

Mueck et al. investigated the behavior of different estrogens combined with progesterone or progestins in breast cancer cells. They found that progesterone inhibited the proliferation of these cells in the presence of high estrogen levels, while synthetic progestins had the potential to stimulate their proliferation when combined with the synthetic estrogens Equilin and 17-alpha-dihydroequilin, present in the conjugated equine estrogens (CEE) used in the WHI study. This demonstrates the mechanism behind the increased risk of breast cancer observed when combining CEE with progestins.

The Nurses’ Health study followed 58,000 postmenopausal women for 16 years, observing a 23% increased risk of breast cancer in women who had used unopposed estrogens (without adding progesterone). When a synthetic progestin was added, the increased risk reached 67%.

Lee et al. conducted a meta-analysis of 61 studies observing an increased risk of breast cancer with the use of synthetic hormones and that higher doses of progestins increased the risk of breast cancer.

Large-scale observational studies and clinical trials in primates give us the difference between bioidentical progesterone and synthetic progestins in terms of breast cancer risk. Progestins have been consistently shown to increase risk and progesterone has been shown to consistently reduce it.

Fournier et al. reported an association between various forms of HRT and the incidence of breast cancer in more than 80,000 postmenopausal women who were followed for more than 8 years. Compared to women who had never used any HRT, women who used estrogen alone (several preparations) only had 1.29 times more of a risk of breast cancer. If a synthetic progestin was used in combination with estrogen, the risk of breast cancer increased significantly to 1.69 times that of control subjects. However, for women who used progesterone in combination with estrogen, the increased risk of breast cancer was eliminated.

In an analysis of more than 50,000 postmenopausal women in the E3N-EPIC cohort, Fournier et al. found that the risk of breast cancer increased significantly if synthetic progestins were used (RR = 1.4), but it was reduced if progesterone was used (RR = 0.9). There was a significant difference in breast cancer risk between estrogen use combined with synthetic progestins versus estrogen combined with progesterone.

Wood et al. studied the use of placebo, estradiol, estradiol and MPA, and estradiol and bioidentical progesterone in postmenopausal primates. They looked at the expression of Ki67, which is a biomarker for lobular and ductal epithelial proliferation in the postmenopausal breast and is an important prognostic indicator of human breast cancer. Compared to the placebo, a significant increase in proliferation was found with the combination of estrogen and MPA in both lobular and ductal tissue, but this was not observed in the combination of estrogen and progesterone.

So with this data, everything seems a bit clearer, right? We’ll mention two other studies before finishing this first part to clarify the role of progesterone.

A prospective epidemiological study showed a protective role for progesterone in preventing breast cancer. In this study, 1,083 women who had been treated for infertility were followed for 13 to 33 years. The premenopausal risk of breast cancer was 5.4 times higher in women who had low levels of progesterone compared to those with normal levels. The result was significant, despite the fact that the group with high progesterone levels had significantly more risk factors for breast cancer than the group with low progesterone content, stressing the importance of this parameter. Additionally, there were 10 times more cancer deaths in the low progesterone group compared to those with normal progesterone levels.

In another prospective study, progesterone levels in the luteal phase were measured in 5,963 women and compared to the subsequent risk of breast cancer. Progesterone was inversely associated with the risk of breast cancer for the highest tertile in comparison with the lowest.

BIBLIOGRAPHY

(1) Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333.

(2) Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701–1712.

(3) Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy post- menopausal women: the Women’s Health Initiative Randomized Trial. JAMA. 2003;289(24):3243–3253.

(4) Porch JV, Lee IM, Cook NR, Rexrode KM, Burin JE. Estrogen-progestin replacement therapy and breast cancer risk: the Women’s Health Study (United States). Cancer Causes Control. 2002;13(9):847–854.

(5) Chang KJ, Lee TY, Linares-Cruz G, Fournier S, de Ligniéres B. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril. 1995;63(4):785–791.

(6) Mueck AO, Seeger H, Wallwiener D. Comparison of proliferative effects of estradiol and conjugated equine estrogens on human breast cancer cells and impact of continuous combined progestogen addition. Climacteric. 2003;6(3):221–227.

(7) Colditz GA, Rosner B. Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses’ Health Study. Am J Epidemiol. 2000;152(10):950–964.

(8) Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst. 2000;92(4):328–332.

(9) Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107(1):103–111.

(10) Wood CE, Register TC, Lees CJ, Chen H, Kimrey S, Cline JM. Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat. 2007;101(2):125–134.

(11) Cowan LD, Gordis L, Tonascia JA, Jones GS. Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiol. 1981;114(2):209–217.

(12) Micheli A, Muti P, Secreto G, et al. Endogenous sex hormones and subsequent breast cancer in premenopausal women. Int J Cancer. 2004;112(2):312–318.

(13) Foidart JM, Colin C, Denoo X, et al. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril. 1998;69(5):963–969.

La entrada Hormone Replacement Therapy and Breast Cancer: Tearing Down Myths through Scientific Evidence. Part I se publicó primero en Neolife.

Progesterone is produced in the corpus luteum of the ovaries, a temporary gland that is developed once the egg is released from the ovary after it has matured. The Replenish study showed an improvement in the quality of life of patients who received this therapy.

Studies show that progesterone is able to reduce hot flashes associated with menopause even in the absence of treatment with estradiol. It is converted into allopregnanolone in the brain, which produces effects on the GABAergic system and induces sleep. Also, when used in conjunction with estradiol, it improves bone mineral density (BMD), among many other benefits.

Dr. Alfonso Galán González – Neolife Medical Team

Is it merely the inevitable companion of estradiol in Hormonal Replacement Therapy for menopause?

Progesterone is produced in the corpus luteum of the ovaries. It’s a temporary gland that is developed once the egg is released from the ovary after it has matured.

The adrenal glands and the uterus may also produce some progesterone. Progesterone helps prepare the body for pregnancy and causes the endometrium to thicken to receive the fertilized egg. If fertilization does not occur, the corpus luteum is destroyed causing a sharp decrease in this hormone, which in turn causes the endometrium to detach, leading to the onset of menstruation. If the egg is fertilized, the corpus luteum is not destroyed and continues to produce progesterone which, among other things, increases the blood supply to the endometrium, which allows nutrients to reach the embryo that is being formed. When the placenta forms, it also produces progesterone. Levels remain high throughout pregnancy.

Use in HRT (Hormone Replacement Therapy)

The known use of progesterone in this type of treatment is to prevent the proliferation of the endometrium and endometrial cancer when we use estradiol to replenish hormonal levels during menopause and to reverse the harmful effects that accompany the climateric, which are widely known (1).

At this point, we’ll consider a number of things related to the additional effects of providing bioidentical progesterone in HRT and the advantages it has over treatments with progestins (synthetic derivatives of non-bioidentical progesterone).

• There are studies that show that it is able to reduce hot flashes associated with menopause even in the absence of treatment with estradiol.
• The REPLENISH study showed an improvement in the quality of life of patients who received this therapy.
• Progesterone is converted into allopregnanolone in the brain, which produces effects on the GABAergic system and induces sleep.
• When used in conjunction with estradiol, it improves bone mineral density (BMD).
• A systematic review of the literature and analysis of studies conducted on women using estradiol with or without progesterone showed that there was no association between taking estradiol alone and the risk of breast cancer; however, the risk was higher when estradiol was combined with synthetic derivatives such as MPA (medroxyprogesterone), norethisterone acetate or levonorgestrel, but not with bioidentical progesterone (2).
• The use of progesterone is not associated with the risk of venous thromboembolism in postmenopausal women. Several studies confirm this and show that the addition of synthetic derivatives of norpregnane are indeed associated with significant risk (3).
• The ELITE study tested the hypothesis of “hormonal timing”, that is, that an early initiation of HRT, rather than a late one, prevents the progression of atherosclerosis. According to their results, women with less than 10 years of menopause who received oral progesterone did not present a progression of the carotid intima-media thickness and these effects did not vary with the addition of progesterone (4). Progesterone also seems to be beneficial in women with myocardial ischemia. A study conducted on women with ischemic heart disease showed that it prolonged the onset of pain and that this time was prolonged by adding progesterone but not synthetic derivatives (medroxyprogesterone) (5).
• It is a well-known fact that oral estradiol increases HDL cholesterol (good cholesterol), decreases LDL (bad cholesterol), and increases triglycerides. These effects don’t seem to occur with the use of transdermal estradiol. The addition of progesterone increases or has no effect on these elements of the lipid profile.
• At the cognitive level, the addition of progesterone to the treatment with estradiol has a neutral effect on the cognitive changes a woman may experience.

In addition to these effects mentioned above, when used in the context of Hormonal Replacement Therapy (HRT) in menopause, progesterone is very beneficial in premenopausal women as it combats PMS symptoms, and decreases swelling and headaches associated with the menstrual period (6).

In terms of sexual arousal, a study shows that progesterone increases the activity of nitric oxide synthases, thus increasing vaginal relaxation and vascular blood flow in sexual arousal. Its effect on the GABAergic system would also intervene in sexual motivation.

At Neolife, we understand the various beneficial effects of this hormone, all of which we have tried to present in this article. We are proud to help many women by including it in their treatments.

BIBLIOGRAPHY

(1) Mirkin S. Evidence on the use of progesterone in menopausal hormone therapy. Climacteric. 2018 Aug;21(4):346-354.

(2) Cordina-Duverger E, Truong T, Anger A, et al. Risk of breast cancer by type of menopausal hormone therapy: a case-control study among post-menopausal women in France. PLoS One 2013;8: e78016

(3) Canonico M, Fournier A, Carcaillon L, et al. Postmenopausal hor- mone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol 2010;30:340–5

(4) Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early 48. versus late postmenopausal treatment with estradiol. N Engl J Med 2016;374:1221–31

(5) Rosano GM, Webb CM, Chierchia S, et al. Natural progester- one, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol 2000;36:215–19

(6) Wyatt K, Dimmock P, Jones P, Obhrai M, O’Brien S. Efficacy of progesterone and progestogens in management of premenstrual syndrome: systematic review. BMJ 2001;323(7316):776‐80.

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An endocrine disruptor is a chemical substance capable of altering hormonal balance and, consequently, contributing to the increase of certain types of tumors, malformations, reproductive system dysfunctions, neurotoxicity and immune response failure.

Endocrine disruptors are different molecules widely used in our daily lives. The European Parliament’s Policy Department for Citizens’ Rights and Constitutional Affairs has published a scientific report entitled, “Endocrine Disruptors: From Scientific Evidence to Human Health Protection”, at the request of the European Parliament’s Committee on Petitions.

Dr. Celia M. Gonzalo Gleyzes – Neolife Medical Team

What is an endocrine disruptor and where are they found?

The definition of endocrine disruptor (ED) has been included in European regulations since 1999. The study of these substances is particularly important because of the unintended effects on human health in the environment.

An endocrine disruptor is a chemical substance capable of altering hormonal balance and, consequently, contributing to the increase of certain types of tumors, malformations, reproductive system dysfunctions, neurotoxicity and immune response failure. The effects of endocrine disruptors can be direct or synergistic (the accumulation of different EDs could lead to intensified negative effects) (2).

Unfortunately the list of where they are found is long: we can find endocrine disruptors in products we use in our daily lives. such as in food, water, shampoo, toothpaste, fertilizers, tissues, carpets , utensils, toys, cosmetics, deodorant, etc.

We can come into contact with these harmful substances in various ways: by intake, inhalation and by skin absorption.

Endocrine disruptors affect:

• Reproductive health:

It has been shown that exposure, during intra- and extrauterine life, to bisphenol A (BPA), a compound frequently used in plastics and food wrappers, can affect the ovaries and fetal brain development. The endocrine system is especially important for male reproductive development, as androgens (such as testosterone) promote the maturation of secondary male characteristics as well as the spermatogenesis process.

The quality of the seminograms and testosterone levels are deteriorating. Some authors associate this with an increase in the variety of endocrine disruptors such as the compounds perfluorinated compounds (PFCs). Differences have been observed between rural and urban areas, and there is a statistical correlation between poor sperm quality and elevated levels of endocrine disruptors from pesticides (alachlor, diazinon, atrazine, metolachlor and 2,4-dichlorophenoxyacetic acid) (4).

• Brain and thyroid:

Exposure to endocrine disruptors during pregnancy increases the risk of low IQs and neurodevelopmental disorders, such as autism and ADHD, among others.

This finding was published by the European Chemicals Agency (ECHA) itself in its interview with Barbara Demeneix, author of the book “Toxic Cocktail: How Chemical Pollution Poisons Our Brains” (Oxford University Press, 2017).

Levels of thyroid hormones determine the correct development of the fetal brain, especially during the first three months of life.

During this stage, the thyroid gland has not fully developed, so the fetus depends on its mother providing thyroid hormone.

If the mother has a low thyroid hormone level, or reduced access to it due to the effect of the hormonal pollutants, the fetus will not be able to compensate for this deficiency, increasing the likelihood of autism and lower IQ (5.6).

• Increased risk of breast cancer:

A recent study published in the Journal of the National Cancer Institute found that exposure to the pesticide DDT was associated with breast cancer.

Women exposed before age 14 (particularly from birth to age 3) were more likely to develop premenopausal breast cancer. Those exposed after childhood had an increased risk of developing cancer between the ages of 50 and 54.

Another study showed that all the phenolic endocrine disruptors that were analyzed significantly increased the activity of aromatase (enzyme that converts testosterone into estradiol) and the biosynthesis of estradiol in cells suggests a direct link between daily exposure to low doses of these substances and cell proliferation in breast cancer (7,8).

BIBLIOGRAPHY

(1) https://www.aecosan.msssi.gob.es/AECOSAN/web/noticias_y_actualizaciones/noticias/2019/

disruptores_endocrinos.htm

(2) https://www.ehu.eus/XV_SEQA/Resumenes/XVSEQA%20Nicolas%20Olea.pdf

(3) https://www.agenciasinc.es/Multimedia/Infografias/La-contaminacion-invisible-que-altera-las-hormonas

(4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043754/

(5) https://www.ncbi.nlm.nih.gov/pubmed/31274099

(6) https://www.libresdecontaminanteshormonales.org

(7) https://www.medscape.com/viewarticle/909676

(8) https://www.ncbi.nlm.nih.gov/pubmed/30817981

La entrada Endocrine disruptors: an issue today se publicó primero en Neolife.

The problem is not the lack of evidence, but the different way of assessing the scientific evidence of two groups: that of the scientist and that of the doctor. There are several types of studies that are fundamental in terms of the relationship between vitamin D and cancer.

Combining the different studies, the data suggest that having vitamin D in the range of 40-60ng/mL significantly reduces the risk of the onset of, and increases the survival from, many of the most common cancers. To maintain vitamin D in that range, doses between 2,000-5,000 IU per day may be required. It’s not about taking a certain amount, but rather about checking that we are effectively within the protective levels.

Dr. Iván Moreno – Neolife Medical Team

The scientific evidence can be of different kinds. With regard to vitamin D and cancer, there are several fundamental types.

The hypothesis for the relationship between UVB exposure – Vitamin D – cancer is almost 40 years old [Garland, 1980]. There are 5,293 publications with cancer and vitamin D or 25-hydroxy-vitamin D [25 (OH) D] in the title or abstract as recorded in pubmed.gov as of January 30th 2019. However, this hypothesis has not been widely accepted; in fact, since the publication of the results of the VITAL study (VITamin D and OmegA-3 TriaL [Manson, 2019], support for this relationship has been further curtailed. As we will discuss here, the problem is not the lack of evidence, but the different way of evaluating the scientific evidence of two groups: that of the scientist and that of the doctor.

Ecological studies.

The type of evidence used primarily to generate hypotheses is the geographical ecological study. In this approach, populations are defined by their geographic location and the rates of cancer that appear in both are compared, in addition to correlating them with the rates of sun exposure to UVB and other factors modifying the onset of cancer. This approach has identified up to 20 cancers in which there is an inverse correlation between the higher level of sun exposure and the lower mortality from these cancers in countries near the equator [Moukayed, Grant, 2013]. But since these types of studies can’t prove causality, but rather association, critics question-rightly-that perhaps other factors could explain the findings.

Observational studies.

Another type of studies are those known as “observational” studies. In these participants are usually included in cohorts or follow-up groups, with the levels of vitamin D being determined at the beginning and a follow-up over years to check for the possible appearance of tumors and a possible difference in the percentage of appearance between the groups according to different levels of vitamin D. These studies have found a strong inverse correlation between lower vitamin D values ​​and greater appearance of colorectal cancer [Garland, Gorham, 2017], and less clearly but also related, with breast cancer [Grant, 2015], [Grant and Boucher, 2017]. The critics of these results argue that perhaps the relationship is the other way around: i.e. it’s the cancer that diminishes the vitamin D and the low vitamin the one that facilitates the cancer. There is no evidence that this happens in studies aimed at this, but it’s an argument that has gained force when it comes to explaining why, in some clinical trials in which vitamin D was given, the appearance of tumors was not reduced [Autier, 2017].

Studies of biological mechanisms.

A third type of study is the one that seeks to discover what in science is called “biological plausibility”, i.e. discovering the specific mechanism by which vitamin D may reduce the risk of dying from cancer . These mechanisms are well known to date, and can be grouped into those that reduce incidence, angiogenesis and metastatic spread [Moukayed, Grant, 2013], [Moukayed, Grant, 2017].

Genetic studies.

A fourth type of study involves using the data provided by people who have a mutation in the genes that regulate vitamin D levels [Zheng et al. 2017]. The advantage is that diet or sun exposure doesn’t interfere with these studies, so the possible causal relationship could end up being clearer. Unfortunately, mutations have very little effect on the levels of vitamin D, and would thus require large numbers of people with mutations that are in themselves already infrequent. There are several studies but no conclusive results, probably related to the insufficient strength of the studies for the reasons already described [Ong, 2018].

Controlled and randomized clinical trials.

This is the type of clinical study most frequently used in medicine. Two similar groups, and an intervention that is done at random without the patients or the doctors knowing who is receiving the vitamin and who the placebo.

One of the most important limitations of these studies with vitamin D, unlike drugs, is that our body already has vitamin D in itself, and the improvement in levels (and therefore, the possible positive impact in reducing cancer) are not the same if we administer it to a person who had very low levels or higher ones.  With this limitation in mind, it was already appreciated that the right way to conduct studies with vitamin D was to evaluate its previous levels [Heaney, 2014], [Grant et al. al., 2018] . With this idea in mind, we will evaluate the different studies to date.

The first clinical trial showing the benefits of supplementation with vitamin D in cancer prevention was carried out in 2007, where they compared the administration of vitamin D + calcium, calcium alone and placebo. In this study they found a 60% reduction in the appearance of cancer. Both the levels of vitamin D at the beginning and the supplementation with vitamin D proved to be a predictor of the appearance of cancer. [Lappe, 2007].

The second study that showed benefit was a reanalysis of data from an extensive study in women, the Women’s Health Initiative. In a group of 15,000 women, those who hadn’t been taking calcium/vitamin D previously (and with low levels), were given calcium and vitamin D supplements (43% of all the women). The results showed a statistically significant reduction of total and breast cancer of around 14-20%. [Bolland, 2011].

The third major study that showed the benefit of vitamin D was conducted in 2017. In this study, the population was slightly overweight and had an average vitamin D level of 33ng/mL. 2,000 IU of vitamin D was administered with calcium or placebo. The group with vitamin D had an incidence of cancer of 4%, and the group with placebo of 6%, although they were not statistically significant differences. In an in-depth analysis, it was found that women who had indeed improved their levels from under 30 to 30-55ng/dL had reduced the incidence of cancer by 35%. It’s not as important how much vitamin D we give, but if we actually manage to improve the patients’ levels [Lappe, 2017].

The most recent study on vitamin D and cancer was the VITAL study (VITamin D and omega-3 TriaL [Manson, 2019]. This study had more than 25,000 patients, half of which received 2,000 IU of vitamin D and the other half received a placebo.

After a follow-up of 5.3 years, the study showed the appearance of cancer in 1617 participants, 793 with vitamin D and 824 with placebo, a difference that was not statistically significant. The conclusion communicated was that there is no difference in the appearance of cancer with vitamin D. The policy of the journal that published the VITAL study (The New England Journal of Medicine) is understandable in that it only publishes one major result from each study. What’s not so understandable is that the rest of the results that are statistically significant and very relevant in order to understand the role of vitamin D have not been communicated, specifically:

• The group with vitamin D had a 17% lower mortality rate from dying from cancer, which was higher (25%) if the cancers detected in the first two years were excluded (i.e. being understood that they were already there before the start of the study).
• For those who were overweight, the risk of invasive cancer was 14% lower, and for those who were not overweight 26% lower (a dose of 2,000 IU has a greater impact on the blood levels of vitamin D in a person with less weight).

Unfortunately, most of the general media and even the medical media only extract information from the abstract of the study (a brief summary that is included in each article), and have stopped reporting the benefits of vitamin D.

The baseline values ​​(before treatment) were 28ng/mL in men and 32ng/mL in women.

Another factor that has contributed to the error when analyzing the results, is that the VITAL study was designed before the importance of measuring the levels of vitamin D prior to beginning the study was corroborated. The baseline values ​​of 25,000 people were estimated by measuring only the levels in 395 males and 441 females. This was a missed opportunity to assess the hypothesis that vitamin D effectively protects against cancer in those people in whom the values do increase significantly.

Another error in the study was that at the time of its design a possible toxicity of vitamin D at high doses was raised, which although later proven not to be the case, led the directors of the study to use intermediate doses of vitamin D (2,000 IU). ) instead of the 4,000 that other previous studies considered beneficial [Ross, 2011] [Grant, 2016].

The association GrassrootsHealth.net has taken the initiative to study the effect based on the previous levels and those obtained after the supplementation with vitamin D. They have confirmed strong and statistically significant reductions in cancer risk (67%) when comparing levels greater than 40ng/dL with levels below 20ng/dL [McDonnell, 2016]. In a second, larger study, they found an 80% reduction in breast cancer with levels greater than 60ng/dL versus those under 20ng/dL [McDonnell, 2018].

Discussion

Reviewing the literature, the first ecological studies were based primarily on death rates for cancer, in which the impact of vitamin D is greater than on the rates of appearance of a new cancer.

However, on combining the different studies the data suggest that having vitamin D in the range of 40-60ng/mL significantly reduces the risk of the onset of, and increases the survival from, many of the most common cancers.

To maintain vitamin D within this range, doses between 2,000-5,000 IU per day may be required, depending on many factors. As the studies have confirmed, it’s not about taking a certain amount, but rather about checking that we are effectively within the protective levels.

Apart from cancer, vitamin D has many other protective roles at the immune level, in bone protection and even in telomere shortening. Our genetic aging is lower if vitamin D levels are between 50 and 80ng/dL

Both biologists and doctors defend the need to have a scientific approach, considering the wide range of available evidence. For example, by following Hill’s criteria to demonstrate causality, the relationship between vitamin D and cancer prevention satisfies these [Grant, 2009 ; Mohr, 2012]. Far from falling into conspiracy theories that explain the lack of acceptance by the medical community of the proven benefits of vitamin D, which we can find in some forums suggesting that “medicine benefits from keeping us ill”, there are other causes that explain this resistance .

• Physicians are accustomed to analyzing the results of the effect of drugs in clinical trials. The problem is that the effect of vitamins and other essential nutrients can’t be analyzed in the same way. They are substances and nutrients that our body already has, and the design of the studies and their interpretation needs to be different.
• Unfortunately, medical training doesn’t usually go deeply into nutrition and into the relevance of micronutrients.
• Time is scarce when attempting to be constantly up to date in medicine, so doctors often fall into the mistake of reading only the abstracts of the studies without being able to analyze the results in detail. In cases such as the VITAL study, they give us only a partial view of the topic.
• In this age of excess information, we’re accustomed to receiving insistent information through the drug companies’ usual channels: a lot of repetition, visits by medical representatives, conferences, talks by experts in the subject, etc. This type of dissemination requires a lot of investment, which isn’t possible when they’re not drugs but vitamins and nutrients.

So there are a whole series of reasons why this disagreement exists, and a solution to the question of vitamin D and cancer that will have to come sooner or later: a well-performed study with measurement of levels before and after supplementation with good doses of vitamin D, increasing them if necessary until protective levels (50-80ng/dL) are achieved.

Meanwhile, and in light of the results, at Neolife we recommend supplementing with a dose that can be personalized, in order to achieve good levels that protect us adequately.

BIBLIOGRAPHY

(1) Autier P, Mullie P, Macacu A, Dragomir M et al. (2017) Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials.Lancet Diabetes Endocrinol. 5:986-1004. https://www.ncbi.nlm.nih.gov/pubmed/29102433

(2) Bolland MJ, Grey A, Gamble GD, Reid IR. (2011) Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women’s Health Initiative (WHI) limited-access data set.Am J Clin Nutr. 94:1144-1149. https://www.ncbi.nlm.nih.gov/pubmed/21880848

(3) Garland CF, Garland FC. (1980) Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 9:227-231. https://www.ncbi.nlm.nih.gov/pubmed/7440046

(4) Garland CF, Gorham ED. (2017) Dose-response of serum 25-hydroxyvitamin D in association with risk of colorectal cancer: A meta-analysis. J Steroid Biochem Mol Biol. 168:1-8. https://www.ncbi.nlm.nih.gov/pubmed/27993551

(5) Grant WB, Boucher BJ. (2017) Randomized controlled trials of vitamin D and cancer incidence: A modeling study. PLoS One. 12(5):e0176448. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176448

(6) Grant WB, Boucher BJ, Bhattoa HP, Lahore H. (2018) Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations.J Steroid Biochem Mol Biol.177:266-269. https://www.ncbi.nlm.nih.gov/pubmed/28842142

(7) Grant WB, Karras SN, Bischoff-Ferrari HA, Annweiler C, Boucher BJ, Juzeniene A, Garland CF, Holick MF. (2016) Do studies reporting ‘U’-shaped serum 25-hydroxyvitamin D–health outcome relationships reflect adverse effects? Dermato-Endocrinology. 8: e1187349. https://www.ncbi.nlm.nih.gov/pubmed/27489574

(8) Grant WB. (2009) How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer? An examination using Hill’s criteria for causality. Dermatoendocrinol. 1(1):17-24. https://www.ncbi.nlm.nih.gov/pubmed/20046584

(9) Grant WB. (2015) 25-Hydroxyvitamin D and breast cancer, colorectal cancer, and colorectal adenomas: case-control versus nested case-control studies, Anticancer Res. 35:1153-1160. https://www.ncbi.nlm.nih.gov/pubmed/25667506

(10) Heaney RP. (2014) Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 72:48-54. https://www.ncbi.nlm.nih.gov/pubmed/24330136

(11) Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. (2007) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial.Am J Clin Nutr. 85:1586-1591. https://www.ncbi.nlm.nih.gov/pubmed/17556697

(12) Lappe J, Watson P, Travers-Gustafson D, Recker R et al.(2017) Effect of Vitamin D and calcium supplementation on cancer incidence in older women: A randomized clinical trial.JAMA. 317:1234-1243. https://www.ncbi.nlm.nih.gov/pubmed/28350929

(13) Manson JE, Bassuk SS, Lee IM, Cook NR et al. (2012) The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease.Contemp Clin Trials. 33:159-171. https://www.ncbi.nlm.nih.gov/pubmed/21986389

(14) Manson JE, Cook NR, Lee IM, Christen W et al. VITAL Research Group. (2019) Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease.N Engl J Med. 380:33-44. https://www.ncbi.nlm.nih.gov/pubmed/30415629

(15) McDonnell SL, Baggerly C, French CB, Baggerly LL, Garland CF, Gorham ED, Lappe JM, Heaney RP. (2016)Serum 25-Hydroxyvitamin D Concentrations =40ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study.PLoS One. 11(4):e0152441. https://www.ncbi.nlm.nih.gov/pubmed/27049526

(16) McDonnell SL, Baggerly CA, French CB, Baggerly LL et al. (2018) Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations =60 vs < 20ng/ml (150 vs 50nmol/L): Pooled analysis of two randomized trials and a prospective cohort.PLoS One. 13(6):e0199265. https://www.ncbi.nlm.nih.gov/pubmed/29906273

(17) Mohr SB, Gorham ED, Alcaraz JE, Kane CI et al. (2012) Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria?Dermatoendocrinol. 4(2):152-7. https://www.ncbi.nlm.nih.gov/pubmed/22928071

(18) Moukayed M, Grant WB. (2013) Molecular link between vitamin D and cancer prevention. Nutrients. 5:3993-4023. https://www.ncbi.nlm.nih.gov/pubmed/24084056

(19) Moukayed M, Grant WB. (2017) The roles of UVB and vitamin D in reducing risk of cancer incidence and mortality: a review of the epidemiology, clinical trials, and mechanisms. Rev Endocr Metab Disord. 18:167-182. https://www.ncbi.nlm.nih.gov/pubmed/28213657

(20) Ong JS, Gharahkhani P, An J, Law MH, Whiteman DC, Neale RE, MacGregor S. (2018) Vitamin D and overall cancer risk and cancer mortality: a Mendelian randomization study.Hum Mol Genet. 27:4315-4322. https://www.ncbi.nlm.nih.gov/pubmed/30508204

(21) Ross AC, Manson JE, Abrams SA, Aloia JF. (2011) The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.J Clin Endocrinol Metab. 96:53-58. https://www.ncbi.nlm.nih.gov/pubmed/21118827

(22) Zheng J, Baird D, Borges MC, Bowden J. (2017) Recent Developments in Mendelian Randomization Studies. Curr Epidemiol Rep. 4:330-345. https://www.ncbi.nlm.nih.gov/pubmed/29226067

(23) Richards JB, Valdes AM, Gardner JP, Paximadas D, Kimura M, Nessa A, et al. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. The American Journal of Clinical Nutrition. 2007 Nov;86(5):1420–5. https://www.ncbi.nlm.nih.gov/pubmed/17991655

La entrada Vitamin D reduces the risk of cancer. Why do scientists accept this and doctors don’t? se publicó primero en Neolife.

Melatonin is produced in the pineal gland, located deep in the brain and which was considered a possible receptacle for the soul in the early stages of neuroanatomy.

This molecule has been the subject of numerous studies since the 80s and, little by little, we’ve been finding out the surprising effects it has. These are not just limited to sleep, but throughout the body. We could even stretch to say that sleep improvement plays a secondary role to the rest of the benefits.

Dr. Iván Moreno – Neolife Medical Team

Now we’re going to look at the different benefits melatonin has.

This recently discovered molecule (1958), has been the subject of numerous studies since the 80s and, little by little, we’ve been finding out the surprising effects it has. These are not just limited to sleep, but throughout the body. We could even stretch to say that sleep improvement plays a secondary role to the rest of the benefits.

Melatonin is produced in the pineal gland, located deep in the brain and which was considered a possible receptacle for the soul in the early stages of neuroanatomy. There is melatonin in many species of animals and plants, which shows its basic importance in the metabolism of living beings.

High concentrations of melatonin have been found in the retina, gastrointestinal tract, bone marrow, skin and other tissues. We can therefore deduce that it may have an influence on other physiological functions through local secretion and that, far from being just a sleeping aid, melatonin has multiple effects throughout the body, including:

• Regulating the different biological clocks of the body: biological neural clocks are adjusted in cycles more or less approximate to the duration of the day (22-26 hours), but the other daily cycles of the organism such as hepatic metabolism, renal, oxidative stress, body temperature and muscle toning have less accurate clocks so they require internal synchronization. That is why when we suffer jetlag, we’re not only tired, but we feel almost sick – our body does not work properly.
• Control of oxidative stress: melatonin plays a key role in promoting the excellent health of mitochondria and an adequate control of oxidative stress.
• Prevention of dementia.
• Maintenance of the optimal neuronal state.
• Others…

The secretion of melatonin is influenced by external light through the optic nerve. This means nature allows us to synchronize with seasonal changes.

Each of us has a particular predisposition for melatonin secretion, the most frequent being the average that begins producing melatonin at around 8:00 in the evening and peaks about 2:00-3: 00 in the morning.

Quite often we find, when studying the secretion profile, a lack of coordination and insufficient secretion.

These phase imbalances and deficits in the total effect of melatonin cause the appearance of chronobiotic rhythm alterations, imbalance and oxidative stress, etc.

As we age, melatonin secretion drops in quality, resulting in imbalances of the circadian cycles and quantity thereof (figure attached).

Although the doses normally found in supplements are around 2mg, these doses are too small to reach all tissues and serve the different purposes that melatonin has. In addition, in case of using an incorrect dose we can produce the opposite effect (insomnia or de-regulation), which is why taking melatonin supplements without measuring precisely normally only goes well for some people while others report insomnia and discomfort.

At Neolife we advocate taking high doses of melatonin, which have the maximum beneficial effects, but at a personalized dose and at a specific time which will be most beneficial (and which will avoid side effects). For this reason, in collaboration with the International Institute of Melatonin, we conducted studies of melatonin profiles and oxidative stress to be able to prescribe melatonin and antioxidants properly.

Age Management Medicine Group

Recently at the annual meeting of the AMMG in Orlando, Florida, attended by part of the Neolife medical team, results from several studies were presented which showed an antineoplastic effect from high doses of melatonin. In this post we want to review some of the most important ideas that were presented:

• • There is no such thing as “high doses” of melatonin. Melatonin has been shown to be extremely safe and toxic levels of it have not yet been shown. This does not mean that we can take high doses without conducting a previous study, as even if we do not have to avoid the toxicity, we still need to pay attention to the balance of the system.
  • Exposure to blue spectrum light is the most related to the secretion of melatonin. To secrete melatonin, you do not need to sleep, you only need to be in the dark. Professor Ritter went on to say that light at night “is a drug” in relation to the harmful effects it has. This is of extreme importance as the secretion of melatonin and the preparation for an adequate night’s rest begins hours before going to bed (normally at 08:00pm). Maintaining good sleep hygiene and adapting screens to avoid blue light is essential to preserve our melatonin secretion as long as possible.
  • Melatonin and all its metabolites have a powerful effect by capturing free radicals, which are highly toxic and damage DNA, leading to degenerative, autoinflammatory and oncological diseases. It has been seen in different studies that there is a higher incidence of cancer in workers on night shift, or with alterations in the important hourly rhythms (many transoceanic journeys). In fact, light at night is included as a carcinogen by the World Health Organization.

• There is strong scientific evidence that shows that tumors appear, develop and metastasize more easily in subjects exposed to night light that prevents correct melatonin secretion.
• Melatonin inhibits many of the mechanisms that cancer cells use (Hanahan, 2011) and improves sensitivity to chemotherapy.

Following this excellent presentation and reviewing the relationship of melatonin with the appearance of tumors, specifically the breast, in greater depth we have found important scientific evidence that supports this relationship in human studies, showing a clear benefit in prevention and even by adding melatonin to the oncological treatment of breast tumors.

In an extensive review published in the journal Critical Reviews in Oncology last year, it was concluded that there is considerable evidence to support the multiple tumor suppressive effects of melatonin, showing a protective effect against chemotherapy and antitumor of melatonin, especially through its anti-gonadotropin and antiestrogenic effect on the breast tumor.

Due to its low toxicity even in high doses and the full range of benefits that it seems to have shown, melatonin can be considered as a complementary therapy to usual chemo and radiotherapy and in prevention of breast cancer in women with a history of risk or mammary fibrocystic disease.

So then, beyond the benefits for quality of sleep, melatonin is a true antiaging molecule, while allowing vital systems to continue optimum functioning and delaying the appearance of diseases – exactly what Age Management medicine and Neolife are about.

BIBLIOGRAPHY

(1) Kubatka P, Zubor P, Busselberg D, Kwon TK, Adamek M, Petrovic D, et al. Melatonin and breast cancer_ Evidences from preclinical and human studies. Critical Reviews in Oncology / Hematology. Elsevier; 2018 Jan 8;122:133–43.

(2) Majidinia M, Reiter RJ, Shakouri SK, Research IMA, 2018. The multiple functions of melatonin in regenerative medicine. Elsevier.

(3) Shirani A, JCSM ELJOCSM, 2009. Illuminating rationale and uses for light therapy. Journal of Clinical Sleep Medicine.

La entrada Melatonin at high doses protects against cancer se publicó primero en Neolife.

Progesterone is becoming one of the most hopeful treatment options for patients suffering from this disease.

Progesterone is one of the “female sexual” hormones secreted by the ovaries; it is fundamentally cyclical, with a secretory peak from day 13-16 of the cycle, and a sharp fall 1-2 days before the menstrual period begins. This hormone is beneficial both in premenopausal women, due to its relief of premenstrual syndrome, and in postmenopausal women, where it balances the proliferative action of estrogen and mitigates symptoms such as headaches, mood swings or insomnia.

Dr. Francisco Martínez Peñalver – Neolife Medical Team

Currently there is research being conducted into some progestogens that may be useful in the battle against breast cancer.

In medicine it is very common for young doctors to inherit “dogmas of faith” from our teachers – red lines that should never be crossed, and that serve as a basis on which to build the rest of our knowledge.

Very occasionally this knowledge, that is accepted without doubt, is proven wrong by the scientific literature. A small earthquake occurs in the medical world, since it involves changing some of the main principles that govern our daily practice and our medical knowledge.

To this we should add that as technology advances we are becoming more aware that in the human body there is little “bipartisanship”, there is little “black or white”. The samemolecule, the same cell, in different locations, even at different times, acts in a totally opposite way. The basis of all this is the adaptive mechanism that for thousands of years has been modeling the human being, seeking to turn it into a perfect machine capable of acclimatizing to the different circumstances that are going to affect it in the process of living.

One of these paradigms of medicine that is currently close to being torn down is that of Progesterone. Progesterone is one of the “female sexual” hormonessecreted by the ovaries; it is fundamentally cyclical, with a secretory peak from day 13-16 of the cycle, and a sharp fall 1-2 days before the menstrual period begins.

Between the early 1990s and 2002, virtually all the literature produced about hormone replacement therapy was based on the largest epidemiological study ever conducted, the WHI (Women’s Health Initiative ) (1). The conclusions published by this study from 1989 to 2002 were devastatingly against hormone therapy . Not only did the incidence of cardiovascular events increase, but the incidence of breast cancerand cancer of the uterus increased exponentially in the patients who underwent the therapy.

Over the years, however, cracks have appeared in these conclusions. The two fundamental ones were that the WHI patients had had more than 10 years since the beginning of the menopause and that those 10 years without protection from theirestrogen already justified the increase in cardiovascular mortality; and a second failure – this much more important – where it was demonstrated that the progesterone analogue administered, Medroxyprogesterone Acetate , not only did not exercise the beneficial actions of progesterone, but that it produced an “excess estrogenic effect”, which is dangerous tohealth. That is to say, that the participants of the study did not represent the population in a truthful manner, and that what was given as an analog to progesterone had the opposite effects (2).

However, whereas the WHI results against the use of hormone replacement therapywere published with a great fanfare in all the newspapers and were front-page news, the news that came after and that annulled the results of the WHI has not been given much attention by the press in general (3).

For all these reasons, the image we have of a drug such as Progesterone is pernicious, and a dark legend has been generated around its use that we doctors who dedicate ourselves to Bioidentical Hormone Replacement Therapy need to disassemble.

To begin with this demystification, we need to take a look at a review of clinical studies published in January 2017 in the journal Nature Reviews Cancer (4). According to this article by directors Carroll and Hickey, the term progestogenshas been used generically to refer to a series of compounds that activate the progesterone receptors and the term progestins for molecules that mimic the activity of progesterone. Progestins, apart from the progesterone functions, have other actions that may increase the risk of breast cancer; hence the confusion. However, there is no study that even suggests the possibility that progesterone can cause breast cancer. Nevertheless, there is indeed currently research being conducted into some progestogens that may be useful in the battle against breast cancer. The conclusions of this article are that progestogens have a beneficial effect in those estrogen-dependent tumors in combination with the new drugs that block these estrogen receptors. In fact, there is a clinical trial under way for breast cancer patients withestrogenic receptors and positiveprogesteronics, in this case with progesterone (5).

Therefore, progesterone is now changing from playing a harmful role with a dark legend behind it, to being one of the most hopeful treatment pathways for patientssuffering from this disease.

At Neolife, according to the most recent scientific evidence, for a long time we have been taking advantage of the benefits of this hormone, progesterone, both in premenopausal women – for the relief of premenstrual syndrome – and in postmenopausal women -where it balances the proliferative action of estrogen and mitigates symptoms such as headaches, mood swings or insomnia.

BIBLIOGRAPHY

(1) https://www.whi.org/about/SitePages/About%20WHI.aspx. WHI website.

(2) Speroff L. Am J Obstet Gynecol. 2003 Sep;189(3):620

(3) Harman SM et al. Is the estrogen controversy over? Deconstructing the Women´s Health Initiative study: a critical evaluation of the evidence. Ann N Y Acad Sci 2005 Jun; 1052:43-56.

(4) Carroll JS Hickey TE. Deciphering the divergent roles of progestogens in breast cancer. Nat Rev Cancer. 2017 Jan;17(1):54-64.

(5) ISRCTN – ISRCTN23662758: A trial looking at progesterone to treat early breast cancer in premenopausal women.

La entrada Progesterone: from villain to hero hormone in breast cancer se publicó primero en Neolife.

Bioidentical testosterone therapy, at the right doses, is completely safe and allows for a correct hormonal restoration. Nevertheless, myths and rumours still circulate despite lacking any scientific evidence.

Some of the misconceptions that abound in the collective imagination are: that testosterone is a “male” hormone; that its only role in women is for sexual desire and libido; that replacement therapy makes women more masculine; that it gives you a deeper (more manly) voice; that it causes hair loss; that it can have adverse side-effects on your cardiovascular system; that it causes aggression; or that it can increase the risk of breast cancer.

Dr. Iván Moreno – Neolife Medical Team

Many of these myths that create such a bad reputation for hormones are in fact extrapolations of the adverse effects seen from taking very high doses of anabolics, which have nothing to do with bioidentical testosterone.

Testosterone therapy is being increasingly used to alleviate symptoms of hormonal deficiency in pre and postmenopausal women.

Although numerous scientific studies show the safety and success of this treatment, rumours and myths have been created, which by sheer force of repetition seem to hold more “influence” despite lacking any supporting medical evidence.

Many of these myths are extrapolations of the adverse effects seen from taking very high doses of anabolics (testosterone derivatives) for other purposes (such as bodybuilding, doping, etc.).

In this article, we refer solely to therapy with bioidentical testosterone (which is identical to a human testosterone molecule) and only at replacement doses which aim to replenish the physiological levels we already had in our youth; this is the standard that governs a correct hormone restoration, which we employ here at Neolife.

Myth 1: Testosterone is a “male” hormone.

While it is true that men have higher levels of testosterone, the most abundant sex hormone present in a women’s body is also testosterone. Oestrogen (typically referred to as the “female” hormone), although present throughout a women’s life, is found in concentrations 10 times lower than that of testosterone. Testosterone, in balance with lower doses of oestradiol, is equally important for both sexes.

Fact: testosterone is the most abundant and biologically active hormone in women.

Myth 2: The only role of testosterone in women is for sexual desire and libido.

Another misconception, given that testosterone receptors are found in practically all tissues of a women’s body. Testosterone and its precursors decrease with age, and pre and postmenopausal women may experience symptoms of androgen deficiency such as: mood disorders, lack of well-being, fatigue, loss of bone density and muscle mass, mental dullness, memory disorders, hot flushes, joint discomfort, and sexual dysfunction etc.

Fact: testosterone is essential to a woman’s physical and mental health.

Myth 3: Testosterone treatment makes women more masculine.

Restoring a woman’s ideal hormone levels (to that which we had between the ages of 18-25 years old) far from making you more masculine, can in fact make you more feminine. Treatment should not be confused with the high supra-pharmacological doses which are administered to patients requiring more drastic changes due to gender issues; in which case, symptoms are still reversible by merely reducing the dosage.

Fact: excluding supra-pharmacological doses, testosterone has no masculinizing effects on women.

Myth 4: Testosterone will make your voice deeper (more masculine).

Hoarseness of voice can affect us at different times due to inflammation or infection of the throat, but is always reversible. There is no procedure whereby testosterone could produce such a phenomenon; even in cases of high doses of other androgens, there is no clear evidence of producing a deeper voice or any irreversible changes to the vocal chords.

Fact: there is no evidence that testosterone changes your voice.

Myth 5: Testosterone causes hair loss.

Hair loss is a complex and multifactorial process which is also genetically determined. “Androgenic” alopecia refers to the similar type of pattern baldness commonly found in men, not referring to the cause, but rather to the defined pattern. In any case, it is dihydrotestosterone (DHT), and not testosterone, which is involved. Obesity and insulin resistance, as well as alcohol, a sedentary lifestyle and some medications, can increase the conversion of testosterone to DHT and oestradiol in the hair follicle.

Approximately one third of women experience brittle hair and hair loss with age, which often coincides with a decrease in testosterone levels. However, there are studies in which hair regrowth has been achieved due to subcutaneous testosterone implants in such women.

Fact: testosterone does not cause hair loss; in fact, in some cases it can improve hair regrowth.

Myth 6: Testosterone has adverse effects at a cardiovascular level.

Unlike synthetic anabolics, there is no evidence that testosterone has any adverse effect at a cardiovascular level. In fact, its replacement has a beneficial effect on the metabolism of glucose and lipids, as well as on the maintenance of “lean mass” in both men and women’s bodies.

The most complete meta-analysis ³ carried out on this topic shows that there is no greater cardiovascular risk with testosterone replacement therapy; in fact, a lower occurrence of cardiovascular disease has been demonstrated in some groups (those presenting a higher cardiometabolic risk).

Fact: there is substantial evidence supporting the cardiovascular safety of testosterone, which even indicates a likely protective effect.

Myth 7: Testosterone damages the liver and can cause “clotting” (venous thromboembolic disease).

This is an “imported” rumour from the world of anabolic (synthetic androgens) over-use, which when taken orally in high doses, can in effect, cause liver damage. The truth is that parenteral testosterone (gels, skin patches or subcutaneous implants) avoids that first step through the liver and thus has no adverse effects (i.e. there is no increase in transaminase enzymes nor any alteration to the factors that affect blood clotting). There is therefore no relationship between testosterone administered in this way and the occurrence of blood clots (thrombosis, embolism), unlike synthetic steroids, or oestrogens taken without progesterone and progestins.

Fact: non-oral testosterone does not damage the liver or increase blood clotting.

Myth 8: Testosterone causes aggression.

Although the use of anabolics at high doses can cause aggression and attacks of “rage” (hence the rumour), this does not happen with testosterone. Even with supra-pharmacological doses of intramuscular testosterone, there has been no clear onset of aggression.

As has been previously mentioned, in cases of obesity, alcohol consumption, or a marked sedentary lifestyle, the conversion rate of testosterone to oestradiol can be seen to increase. The effects of excess oestrogen (oestradiol and its derivatives) however, have been associated with irritability and aggression in other species. In fact, in women presenting symptoms of androgen deficiency, treatment with testosterone has been shown to improve anxiety and irritability in more than 90% of cases².

Fact: testosterone therapy is not linked to aggression; even in women suffering from testosterone deficiency, therapy improves anxiety and irritability.

Myth 9: Testosterone may increase the risk of breast cancer.

Since 1937, it has been known that the development of breast cancer is usually dependent on oestrogen. Testosterone, however, could play a possible role in slowing down the growth of breast tissue, and may even be a treatment for breast cancer.

In recent studies, in which testosterone was administered together with an aromatase inhibitor (preventing any conversion into oestrogen), they found the tumour to reduce or even disappear⁵.

Fact: testosterone does not increase chances of breast cancer; in fact, it could help to prevent it.

Myth 10: the safety of testosterone use in women has not been tested.

Data of treatment at very high doses in transgender patients has existed for more than 40 years, and has shown this treatment to be safe. Any side-effects have been the consequence of oral intake (which is no longer used) or due to the conversion to oestradiol (which is rarely a problem at the doses used for bioidentical hormone replacement).

Fact: the safety of non-oral testosterone use has been well established in women for cases of very long-term treatments.

BIBLIOGRAPHY

(1) Glaser, R., & Dimitrakakis, C. (2013). Testosterone therapy in women: myths and misconceptions. Maturitas, 74(3), 230–234.

(2) Glaser R, York AE, Dimitrakakis C. Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS). Maturitas 2011; 68: 355–61.

(3) Corona G, Rastrelli G, Maggi M. Diagnosis and treatment of late onset hypogonadism: systematic review and meta- analysis of TRT outcomes. Best Pract Res Clin Endocrinol Metab 2013; 27: 557-579.

(4) Hackett, G., Kirby, M., Edwards, D., Jones, T. H., Wylie, K., Ossei-Gerning, N., et al. (2017). British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. The Journal of Sexual Medicine, 14(12), 1504–1523.

(5) Glaser, R., & Dimitrakakis, C. 2015. Testosterone and breast cancer prevention. Maturitas, 82(3), 291–295.

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Statins not only decrease the number of deaths caused by cardiovascular diseases, but they are also likely to protect women from the occurrence of breast neoplasms (malignancies).

Statins have recently been discussed in relation to their anti-oncogenic capacity in a Swedish study presented at the 2017 Breast Cancer Symposium. The authors demonstrated how the administration of statins significantly decreased the number of deaths directly attributed to breast tumours.

Dr. Moisés De Vicente – Neolife Medical Team

Today, statins form the tip of the spear that doctors use in their attempts to manage cardiovascular risks.

Cardiovascular disease is the leading cause of death in developed societies and, as such remains the main scourge of modern healthcare systems. Multiple factors are involved in the development of such diseases, some of them genetic and, as a result, are inherent in our body, whilst others depend on our lifestyle choices.

Hypercholesterolemia is considered one of the main risk factors in the formation of atherosclerotic plaque in our arteries and, as a result, one of the precursors in the development of cardiovascular disease. This fact has been known since the 1950s, but it was not until the 1970s that the active ingredient was discovered that would change the progression and prognosis of this disease forever: the HMG CoA reductase inhibitors, that is to say statins.

It is true that there are many detractors for this type of drugs, mainly due to the side effects associated with the drug.
But in general terms the side effects are rare and the new generation of drugs, have reduced the risk of side effects considerably. One could say that they have been optimized to the greatest extent possible to allow the patient the opportunity to enjoy life with energy whilst decreasing their cholesterol without risking a myopathy, for example.

For that reason, today statins form the tip of the spear that doctors use in their attempts to manage cardiovascular risks, both in terms of primary and secondary prevention. In fact, they are already marketing poly pills that bring together the main active ingredients that have been shown to reduce death rates in this type of patient, such as aspirin, angiotensin-converting enzyme inhibitors (ACE-inhibitors) and, of course, statins.

However, many of these drugs are being re-examined to assess how useful they will be in treating these types of cardiovascular pathologies, whilst considering the many other advantages and functions the pill may have, and the likely effects that can be extrapolated to other diseases that have little or nothing to do with cardiovascular risk factors.

Specifically, statins have recently been discussed in relation to their anti-oncogenic capacity in a Swedish study presented at the 2017 Breast Cancer Symposium. The authors demonstrated how the administration of statins reduced the number of deaths around the world amongst women who were administered the drug. This is to many an obvious outcome, due to the cardiovascular improvements that these drugs are known to cause. Notwithstanding this they also demonstrated that the number of deaths directly attributed to breast tumours also decreased significantly. And, furthermore, this was demonstrated in both women who were already undergoing treatment before diagnosis and in those who started taking statins after the diagnosis.

It is true that this is a retrospective study and the possible limitations that this implies must be taken into account. However, it has shown with statistical significance that those women without any previous diagnosis of breast cancer who were taking statins on a regular basis had a 23% lower risk of dying from breast cancer, compared to those who were not receiving statins. Likewise, those women who had previously been diagnosed with breast cancer had a 17% less chance of dying from the tumour if they were being treated with statins.

Some data from the study required further attention. For example, the dose or type of statin used did not alter the results. Thus, it is clear that administration of high doses is not necessary, which may reduce the risk of side effects as it does not appear to depend on any specific active ingredient. All statins are useful in this regard and effective at safe doses.

It is true that extrapolating from these results to any type of breast tumour is risky and unlikely to be accurate. Certain types of tumours express the HMG CoA reductase enzyme and it is thought that it is through this mechanism that statins manage to prevent, or at least slow down, the growth of these neoplasms (malignancies). Consequently, it will be in the tumours in which this enzyme is over expressed that the treatment will be most effective. One could even measure the activity of such enzyme in the tumour cells and thus be able to predict in which patients the treatment would be indicated.

On the other hand, the results from this study have shown how the use of statins can also decrease the concentration of a cholesterol metabolite and the important relationship with the estrogenic receptors present in breast tissue. By decreasing the aforementioned metabolite, these receptors are blocked, decreasing the stimulation on the breast and therefore limiting the growth of the tumours. Following this line of argument, a new clinical trial has just started for women diagnosed with breast cancer to assess the effectiveness of a conventional statin, such as Atorvastatin, in managing oestrogen-receptor positive breast cancer (ER positive breast cancer).

In short, the message we must extract from this is that statins are beneficial drugs. Not only do they decrease the number of deaths caused by cardiovascular diseases, but they are also likely to protect women from the occurrence of certain tumours, in this case, breast neoplasms (malignancies).

At Neolife we use all the tools and innovations at our disposal to provide our patients with the best of preventive medicines that exist. We approach cardiovascular risk from a different perspective by trying to obtain levels of excellence in biomarkers that will allow us to defer and even prevent the occurrence of the dreaded cardiovascular disease. For this the use of statins is of vital importance. But, in addition to this, we also seek to detect and prevent oncological diseases thanks to our unique oncoprevention unit. In this sense, it is likely that the use of statins will become more commonplace in this type of scenario. Future studies are likely to confirm this to be true.

La entrada Statins: the multifunctional drug se publicó primero en Neolife.

A new handheld device – called MassSpec – enables the user to distinguish between healthy tissues and malignant tumours quickly and reliably.

The device uses mass spectrometry similar in some ways to the technique used in the laboratory, without having to use any reagents or cause damage to the tissue. The device simply extracts tiny samples of tissue in order to characterize the proteins, lipids and metabolites thereof. The device is placed on the sample and activated using a foot control and within 10 seconds the tissue identification process is completed.

Dr. Francisco Martínez Peñalver – Medical Director, Neolife Marbella

Despite the relatively short time-frame the MassSpec device provides an accuracy of 96.3% (on average) when identifying malignant tissues depending on their location.

Normally the Pathological Anatomy departments of any given hospital take days and even weeks in some cases to provide such a diagnosis which in turn delays the start of the treatment(s). The process of identifying a sample is long and tedious as it is necessary to carry out a series of preparations prior to examination under the microscope by a specialist doctor. On the other hand, it is equally possible that the samples that are sent to be analysed include only healthy tissue and do not contain part of the tumorous tissue that cause disease.

Recently, researchers at the University of Texas have published their results on the use of a handheld device called MasSpec Pen which allows the user during the course of an operation to distinguish between healthy tissues and malignant tumours quickly and reliably. Despite the relatively short time-frame the MasSpec Pen provides an accuracy of 96.3% (on average) when identifying malignant tissues depending on their location.

How to detect cancer in 10 secondsalt At present research is being undertaken at the Texas Medical Center on the different subtypes of lung cancer, breast cancer, ovarian cancer and papillary and follicular thyroid cancer in mice and the results have accelerated efforts to commence clinical trials in patients already diagnosed with cancer at the beginning of 2018. The device uses mass spectrometry similar in some ways to the technique used in the laboratory, without having to use any reagents or cause damage to the tissue. The device simply extracts tiny samples of tissue in order to characterize the proteins, lipids and metabolites thereof. The device is placed on the sample and activated using a foot control and within 10 seconds the tissue identification process is completed. The cost of this technique is relatively high, but it is less than the other diagnostic tests that these patients may also undergo (MRI, CT, PET etc.). Despite the apparent cost-saving, it is estimated that the device will not be commercially available for a number of years once the human studies have concluded. There have been numerous advances in recent years in the search for effective and reliable diagnostic methods in oncological patients, in terms of increased accuracy and reliability of the results. Perhaps the most developed technique, already in clinical use in some centres, is the so-called “liquid biopsy“. This technique consists of detecting circulating tumour cells and circulating tumour DNA in a blood sample which is promising biomarkers in the area of ​​Oncology but this requires greater knowledge and experience.

What remains undeniably a focus for cancer patients is prevention -most of the risk factors for cancer are well known- and the early diagnosis -through regular check-ups is intended to uncover evidence of early stages of the disease, such as those we perform in the Neolife clinic-.

BIBLIOGRAPHY

(1) Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system. Zhang J1, Rector J1,2, Lin JQ1, Young JH1 Sci Transl Med. 2017 Sep 6;9(406). (2) Liquid biopsy: will it be the ‘magic tool’ for monitoring response of solid tumors to anticancer therapies? Gingras I1, Salgado R, Ignatiadis M. Curr Opin Oncol. 2015 Nov;27(6):560-7 (3) Intraoperative frozen section analysis for the diagnosis of early stage ovarian cancer in suspicious pelvic masses. Ratnavelu ND1, Brown AP, Mallett S, Scholten RJ, Patel A, Founta C, Galaal K, Cross P, Naik R. Cochrane Database Syst Rev. 2016 Mar 1;3:CD010360

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