Research

Sex Hormones Studies

• In a 2013 study: researchers estimated that over the past decade between 18,600 to 91,600 postmenopausal women, ages 50-59 years old, who had had a hysterectomy may have died prematurely because they did not take estrogen.

Sarrel, P., et al., “The mortality toll of estrogen avoidance: An analysis of excess deaths among hysterectomized women aged 50 to 59 years,” Amer Jour Public Health 2013; July 18.

• Meta-analysis from 27 published studies showed a 28% reduction in mortality in menopausal women under age 60 who used hormone replacement therapy and the participants also had improved quality of life.

 Salpeter, S., et al., “Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women,” Amer Jour Med 2009; 22(11):1016-22.

 Studies Regarding Risks of Synthetic Progesterones and Non-Bioidentical Estrogens

• Progestins increase breast cell replication and growth due to the stimulation of estrogen receptors by progestins.

Wood, C., et al., “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):125-34.

Liang, Y., et al., “Synthetic progestins induce growth and metastasis of BT-474 human breast cancer xenografts in nude mice,” Menopause 2010; 17(5):1040-47 Ory, K., et al.,, “Apoptosis inhibition mediated by medroxyprogesterone acetate treatment of breast cancer cell lines,” Breast Cancer Res Treat 2001; 68(3):187-98. 

Papa, V ., et al., “Progestins increase insulin receptor content and insulin stimulation of growth in human breast carcinoma cells,” Cancer Res 1990; 50(24):7858-62.

Rossouw, J., et al., “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):321-33.

Fournier, A., et al., “Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort,” Int Jour Cancer 2005; 114(3):448-54.

Porsch, J., et al., “Estrogen-progestin replacement therapy and breast cancer risk: the Women’s Health Study (U.S.),” Cancer Causes Control 2002; 13(9):847-54.

• Natural progesterone has been shown to decrease the risk of developing breast cancer.  A study looked at 80,000 postmenopausal women for 8 years using different kinds of HRT.   It found that women who used estrogen in combination with synthetic progestin had a 69% increased risk of developing breast cancer when compared to women who never took HRT. Women who used progesterone in combination with estrogen had no increased risk in developing breast cancer compared to women that did not use HRT and also had a decreased risk in developing breast cancer compared to the women that used progestin.

Fournier, A., et al., “Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study,” Breast Cancer Res Treat 2008; 107(1):103-11.

Murkes, D., et al., “Effects of percutaneous estradiol-oral progesterone versus oral conjugated equine estrogens-medroxyprogesterone acetate on breast cell proliferation and bel-2 protein in healthy women,” Fertil Steril 2011; 95(3):1188-91.

Wood, C., et al., “Transcriptional profiles of progesterone effects in the postmenopausal breast,” Breast Cancer Res Treat 2009; 114(2):233-42.

Neubauer, H., et al., “Overexpression of progesterone receptor membrane component 1: possible mechanism for increased breast cancer risk with norethisterone in hormone therapy,” Menopause 2013; 20(5):504-10.

Murkes, D., et al., “Percutaneous estradiol/oral micronized progesterone has less adverse effects and different gene regulations than oral conjugated equine estrogens/medroxyprogesterone acetate in the breast of healthy women in vivo,” Gynecol Endocrinol 2012; 28(Suppl 2):12-5.

Chang, K., et al., “Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo,” Fertil Steril 1995; 63(4):785-91.

Foidart, J., et al., “Estradiol and progesterone regulate the proliferation of human breast epithelial cells,” Fertil Steril 1998; 69(5):963-69.

Mueck, A., et al., “Comparison of the proliferative effects of estradiol and conjugated equine estrogens on human breast cancer cells and impact of continuous combined progestogen addiction,” Climacteric 2003; 6(3):221-27.

• Another study done by the same researchers found a 40% increased risk of developing breast cancer in women who used estrogen with progestin. In women who used estrogen combined with progesterone there was a trend toward a decreased risk of developing breast cancer.

Fournier, A., et al., “Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort,” Int Jour Cancer 2005; 114(3):448-54. 

• Study measured blood levels of progesterone in almost 6,000 women that were premenopausal.  Women with the highest levels of progesterone who had regular cycles had a 88% reduction in the risk of developing breast cancer.

Micheli, A., et al., “Endogenous sex hormones and subsequent breast cancer in premenopausal women,” Int Jour Cancer 2004; 112(2):312-18.

• In another study over 1,000 women were studied for over 30 years who had treatment for infertility. The trial was done to look at subsequent breast cancer risk. Women who were deficient in progesterone had 5.4x increased risk of developing premenopausal breast cancer and were10x as likely to die from any cancer.

Cowan, L., et al., “Breast cancer incidence in women with a history of progesterone deficiency,” Amer Jour Epidemiol 1981; 114(2):209-17.

Studies Regarding Testosterone

*Men with total testosterone <300 ng/dL at single AM draw. Adapted from Mulligan T, et al. Int J Clin Pract. 2006;60(7):762-769. Hypogonadism adversely affects metabolic and cardiovascular risk factors, insulin resistance and endothelial function…

Traish AM, Saaf F, Guay A. J Androl. 2009;30(1):23‐32.

Morley JE, et al. Metabolism. 2000;49(9):1239‐1242;

Bhasin S, et al. J Clin Endocrinol Metab. 2006;91:1995‐2010.

TD and Metabolic Syndrome:A Bidirectional Association of T and Metabolic Syndrome

-Cross-sectional studies report direct correlation between serum T and increased risk of DM (in men…)

-Incidence of metabolic syndrome increases with age, as T and SHBG levels decrease

-Studies demonstrating hypogonadal T levels give 2X increased risk of insulin resistance

-Push to have “hypotestosteronemia” as criterion DM = diabetes mellitus; SHBG = sex hormone-binding globulin.

Pitteloud N, et al. Diabetes Care. 2005;28(7):1636-42;

Grillo ML, et al. Horm Metab Res. 2005;37(11):662-5., p12 T lecture

EPIC-Norfolk: Testosterone Concentrations

Related to All-Cause and CVD Mortality*

*Started in 1993 (~19 years).

CVD = cardiovascular disease; EPIC-Norfolk = european prospective investigation of cancer.

T and CVD –What are the Outcomes?

• Low endogenous T levels associated with increased risk of all-cause and CVD mortality

Araujo AB, et al. J Clin Endocrinol Metab.2011;96(10):3007-19.

• Elevated LH and decreased T predict ischemic heart disease in older men

Hyde Z, et al. Eur J Endocrinol. 2011;164(4):569-77.

• Low free testosterone predicts mortality from CVD but not other causes

Hyde Z, et al. J Clin Endocrinol Metab.2012;97(1):179-89.

Melatonin

Effects of Melatonin on Aging and Memory

• “The human pineal gland and melatonin in aging and Alzheimer’s disease,”

Wu, Y., et al., Jour Pineal Res 2005; 38(3):145-52.

• “Melatonin prevents beta-amyloid-induced lipid peroxidation,”

Daniels, W., et al., Jour Pineal Res 1998; 24(2):78-82.

• “Neuroprotective role of melatonin in oxidative stress vulnerable brain,”, Pandi-Perumal. Gupta, Y., et al., Indian Jour Physiol Pharmacol 2003; 47(4):373-86.
• “Retardation of brain aging by chronic treatment with melatonin,”, Bondy, S., et al.,  Ann NY Acad Sci 2004; 1035:197-215.
• “The use of melatonin in Alzheimer’s disease,” Cardinali, D., et al., Neuro Endocrinol Lett 2002; 23(Suppl 1):20-3.
• “Role of melatonin in Alzheimer-like neurodegeneration,” Wang, J., et al., Acta Pharmacol 2006; 27(1):41-9. 

Melatonin effects regarding Cardiavascular disease and Stroke

• Melatonin has been shown to reduce hypoxia and prevent reoxygenation-induced damage in patients with cardiac ischemia and ischemic stroke.

“Melatonin: a novel protective agent against oxidative injury of the ischemic/reperfused heart,” Reiter, R., et al., Cardiovasc Res 2003; 58(1):10-9.

• “When melatonin gets on your nerves: its beneficial actions in experimental models of stroke,” Reiter, R., et al., Exp Biol Med 2005; 230(2):104-17.
• “Prognostic value of nocturnal melatonin levels as a novel marker in patients with ST-segment elevation myocardial infarction,”

Dominguez-Rodriguez, ., et al.,  Amer Jour Cardiol 2006; 97(8):1162-64.

• “Relation of nocturnal melatonin levels to C-reactive protein concentration in patients with T-segment elevation myocardial infarction,”

Dominguez-Rodriguez, A., et al., Amer Jour Cardiol 2006; 97(1):10-2.

• MARIA study was a prospective, randomized, double-blind, placebo-controlled trial. Used IV melatonin in patients following an acute MI that were having angioplasty.  Showed Decreased CRP and IL-6, Attenuated tissue damage from reperfusion, Decreased V tach and V fib after reperfusion, Attenuated cellular and molecular damage from ischemia

“Clinical aspects of melatonin in the acute coronary syndrome,”

Dominguez-Rodriguez, A., et al., Curr Vasc Pharmacol 2009; 7(3):367-73.