Can 5 Cups of Coffee Boost Testosterone to Estrogen Ratio in Overweight Men Transiently by Almost 200%? Plus: SHBG Its Own Receptor and Its Role in Prostate & Breast Cancer

Testosterone booster in men and estrogen amplifier in women? As if there were not already enough good reasons to get your daily dose of the 'kingly' brew ;-)

You would not have to be a diligent student of the SuppVersity to know: Coffee is a truly remarkable brew. Even mainstream media has gotten wind of the multitude of beneficial effects a moderate intake of the former drink of the kings and popes can have on your health and if it was not for the authors and newscasters blind reliance on whatever the press release guys are telling them, it would probably not even have been necessary for me to broach the beneficial effects coffee can have on your metabolic health and overall well-being in posts like "Coffee - 3 Cups a Day Keep Insulin at Bay", "Pre-Workout Caffeine: Fat Liberator, Substrate Modulator, Trans-Fatty Acid Eliminator & Performance Upregulator!" and many more.

So what is it this time? What else can coffee do for you?

I guess something only few people others than SuppVersity readers will be aware of is the fact that caffeine  and therefore coffee makes a nice testosterone booster (Beavon. 2008; study was discussed briefly as part of a longer post on June 20, 2013 an mentioned previous times in other posts) -- at least if you stick to moderate doses of ~300-400 mg before a workout. So, unless you are a newbie or missed the respective news, you should not be surprised that a recent study from the Harvard School of Public Health (Wedick. 2013), which had actually been designed mainly to investigate the effects of 5x 6-ounze cups caffeinated and decaffeinated coffee (both instant coffees; brand: Nestlé’s Taster’s Choice) on serum levels of sex hormone-binding globulin (SHBG), found that the consumption of both 'real' and 'fake' (=decaffeinated) instant coffee did lead to increases in total and free testosterone and profound decreases in estradiol (bound and free).

Figure 1: Levels of SHBG, testosterone, free testosterone, estradiol, free estrogen, the testosterone to estrogen ratio and DHEA in the male participants of the study expressed relative to a caffeine abstinent control group (based on Wedick. 2013)

As the data in figure 1 goes to show these changes were unfortunately transient and the impressive +189% increase in the testosterone to estrogen ratio which occurred during the first month of treatment totally disappeared within the next four weeks. On the other hand, the effects on SHBG the scientists had expected based on the assumption that both SHBG and caffeine intake have been found to be associated with lower risk of type II diabetes in large epidemiological studies, was non-existent in the first and second 4 weeks of the study... at least in the male subjects who were all overweight, nonsmokers and habitually coffee consumers, who had been required to abstain from caffeine intake for at least 2 weeks before the study was conducted.

Figure 2: Levels of SHBG, testosterone, free testosterone, estradiol, free estrogen, the testosterone to estrogen ratio and DHEA in the female participants of the study expressed relative to a caffeine abstinent control group (based on Wedick. 2013)

If you take a look at the data from the female participants (likewise overweight non-smokers, habitual caffeine consumers and, at the beginning of the study, 'dried out'; see figure 2), a different image emerges, in the women we do in fact see a transient rise in SHBG, which goes hand in hand with a decrease in testosterone, de to which the T/E ratio drops by -36% and -54% in the groups drinking caffeinated and noncaffeinated coffee respectively. Just as in their male counterparts, the levels did go back up in the second part of the study so that all values, including the SHBG levels were back in to normal after 8 weeks (please note changes in the 20% range are irrelevant and could be due to having a meal before the test, bad sleep, whatever).

The relative data tells only part of the story

Figure 4: Absolute values of the testosterone to estrogen ratio after 4 and 8 weeks; baseline levels were 16.2, 15.8, 18.2 in the caffeinated coffee, decaffeinated coffee and control group respectively. The data clearly shows: Coffee needs a PCT ;-)

If we do now take a closer look at the actual data and discard the comparison to the control group the scientists the picture becomes even more complex. After all the data in figure 4 clearly indicates that we are dealing with a combined effect here. It is correct that the ingestion of the caffeinated beverage had pronounced effects on the T/E ratio especially in the male participants, what the data in figure 1 does yet not tell you is the fact that this effect was also so pronounced, because simply stopping to drink caffeine reduced the T/E ratio from 18.1 to 8.4, i.e. by 54%(!).

Now this certainly reduces the effect size, but it does not totally negate the effect. After all the 'real' coffee drinkers (w/ caffeine) did still increase their T/E ratio from 16.2 to 24.2 -- a certainly likewise noteworthy increase of +29% that is however still far away from the exorbitant +189% increase compared to the poor guys who did not just lose their coffee, but also their virility.

So what does this tell use?

How cares about SHBG anyways? You should! After all there is relatively conclusive evidence that normal (not exorbitantly high!) SHGB levels have a protective effect against breast cancer in women and mechanistic evidence that they increase the risk of prostate cancer in men. In both cases SHBG acts independently via the largely ignored SHBG receptor that modulates the action of estrogens. Co-activation of SHBG and estrogen receptor in the prostate induces similar effect on prostate specific antigen secretion as DHT (Nakhla. 1997). Since estrogen alone does not have this effect, it is no wonder that stinging nettle root (Urtica dioica), with its SHGB inhibiting effect is a viable tool in the treatment of benign prostatic hyperplasia (Hryb. 1995). In the female breast, on the other hand, SHBG seems to " trigger a 'biologic' anti-estrogenic pathway" (Fortunati. 1999) and does therefore exert anti-instead of pro-carcinogenic effects.

I guess there are more than just the following three lessons to learn from this study, but at the moment these appear to be the most important ones for me:

1. The beneficial effects habitual coffee intake has on type II diabetes risk are, contrary to the scientists hypothesis, not mediated by its effect on SHBG.
2. In overweight men caffeine has a very shortlived beneficial effect on testosterone and the testosterone to estrogen ratio. After 4 weeks the levels do yet return to baseline, so this cannot explain the long-term benefits of habitual caffeine consumption either (maybe you should cycle caffeine instead of testosterone booster < I am just kidding ;-).
3. In overweight women, there is a similar, yet negative effect on testosterone levels, which is likewise transient and lasts less than 8 weeks. 
4. The caffeine ads to the 'pro-testosterone' effects, but even decaffeinated coffee has some effects.
5. Stopping "cold turkey" is not a good idea, when you are "on caffeine"

Now, what is important here is that we are dealing with overweight individuals, in whom the endocrine millieu is usually off. In particular, men tend to have reduced, women tend to have increased androgen levels (think PCOS). The effects we see after short-term withdrawal and the subsequent consumption of a non-negligible amount of 5 cups of coffee everyday could actually have corrective effects on the endocrine milieu, of which both, men and women could benefit, if they would last for more than 4-6 weeks. The detrimental effects of stopping, on the other hand, could be due to the sudden absence of the benefits of caffeine.

Regardless of whether you stop or start drinking coffeine, the endocrine "disturbances" are relatively short-lived and only further testimony to the fact that our bodies will always try to find a new "steady state" in what they consider normal.

Bottom line: There are a myriad of good reasons to drink coffee, getting more manly or more feminine is yet not one of them. Disappointed? Well, on the other hand this means coffee is no endocrine disruptor - and at least in this overweight population it seems to have a marginally beneficial baseline effects (thus the detrimental effects of abstinence).

References:

• Beaven CM, Hopkins WG, Hansen KT, Wood MR, Cronin JB, Lowe TE. Dose effect of caffeine on testosterone and cortisol responses to resistance exercise. Int J Sport Nutr Exerc Metab. 2008 Apr;18(2):131-41. 
• Fortunati N, Becchis M, Catalano MG, Comba A, Ferrera P, Raineri M, Berta L, Frairia R. Sex hormone-binding globulin, its membrane receptor, and breast cancer: a new approach to the modulation of estradiol action in neoplastic cells. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):473-9.
• Hryb DJ, Khan MS, Romas NA, Rosner W. The effect of extracts of the roots of the stinging nettle (Urtica dioica) on the interaction of SHBG with its receptor on human prostatic membranes. Planta Med. 1995 Feb;61(1):31-2.
• Nakhla AM, Romas NA, Rosner W. Estradiol activates the prostate androgen receptor and prostate-specific antigen secretion through the intermediacy of sex hormone-binding globulin. J Biol Chem. 1997 Mar 14;272(11):6838-41.
• Wedick NM, Mantzoros CS, Ding EL, Brennan AM, Rosner B, Rimm EB, Hu FB, van Dam RM. The effects of caffeinated and decaffeinated coffee on sex hormone-binding globulin and endogenous sex hormone levels: a randomized controlled trial. Nutr J. 2013 Oct 19;11(1):86.

Serious Lifting Increases SHBG, Muscle & Total Mass, While Decreasing Total and Trunk Fat in Overweight Young Men. Plus: Why an Increase in SHBG is Nothing to Be Afraid Of

Warning: Used correctly, this dumbbell will increase your BMI, your glucose sensitivity and - at least if you still got some fat to shed - your SHBG! And what's the result? Metabolic health, strength and a significantly improved body composition!

If you read the headline of today's news closely and did not freak out due to bro-scientific indoctrination and the firmly held believe that "SHGB is bad for you, bro. I'll bind your testosterone, bro!" you will probably have noticed that the 12-week resistance training regimen 36 of the 49 participants (BMI 31.4 kg/m² age 22 years) of a recently published study by Roberts et al. underwent would have to be considered an epic fail, if we went for the mainstream assessment of workout / dietary success - the infamous body mass index. If the add the broscientific notion that you best reduce your SHBG to zero (or into the negative range, if you find a way to do so), squats, deadlifts, lunges, rows, side raises, overhead presses, triceps extensions and biceps curls appear to be the worst thing you can do for your health and physique!

Yep, there is no debating: The overweight guys gained even more weight...

... and this change in BMI was statistically significant (p = 0.03). In kilograms that means the average 21.5 year old member of the resistance training group gained 1.8kg body weight, but at the same time he lost 1kg of body fat, reduced his waist circumference by 0.55cm and gained a whopping 2.7kg of lean body mass (p < 0.0001; see figure 1, right).

Figure 1: Changes in body composition and strength in the course of the 12-week study period (Roberts. 2013)

As the data in figure 1 (left) goes to show, the resistance training protocol, which comprised three pases with a 2-week introductory period of 12-15 reps to failure, a second hypertrophy phase from week 3-7, in the course of which they lifted in the 8-12 rep range and a subsequent heavier lifting phase with 6-8 reps during phase 3 (weeks 8-12).

"As participants adapted to the training overload, the weight was increased to maintain the prescribed training intensity. All participants trained on 3 non-consecutive days/week, rotating between two daily workout regimens. Workout I consisted of dumbbell (DB) squat, cable row, DB front lunge, DB row, barbell (BB) deadlift, DB triceps extension, and DB curl.Workout II was DB step-up, BB chest press, machine squat, DB overhead press, DB incline chest press, DB side raise, DB reverse fly, and abdominal crunches. A certified personal trainer led all training sessions with a maximum 3:1 participant to trainer ratio." (Roberts. 2013)

You see, real training yields real results. And while diets (in the study at hand "participants were instructed tomaintain their normal ad-libitum diet") are necessary to cut weight and lose fat in those who are already lean, healthy (not metabolically deranged) overweight individuals can achieve a whole lot by just lifting their behind off the couch and into the gym thrice a week.

Aesthetics are not all that counts

That said, in addition to the aesthetic improvements due to the changes in body composition, it should not be forgotten that despite the weight gain that would have discouraged many uneducated dieters, the resistance training only program yielded similar beneficial effects as far as the glucose management and insulin sensitivity of the participants is concerned.

Figure 2: Relative (% baseline) changes in response to oral glucose tolerance test (OGGT) and hormone levels after 12 weeks of resistance training (Roberts. 2013)

How and if this has any direct relation to the hormonal changes (figure 2, right) in general and the increase in SHBG, in particular, is as of now, not 100% certain.

"The function of SHBG has classically been ascribed to the binding of steroid hormones in circulation to regulate their bioavailability. Because SHBG is decreased with obesity, it was thought that SHBG may be a marker for obesity in relation to T2D risk. However, evidence suggests that SHBG independently affects glycemic control and predicts both  T2D and metabolic syndrome. In addition, it is known that insulin and glucose also have reciprocal action on SHBG to regulate SHBG production in the liver." (Roberts. 2013)

Despite the fact that the perception of SHBG as an inactive binding protein is changing as of late, the study at hand does not provide clear cut evidence that the improvements in insulin tolerance occur in response to the changes in SHBG. This result matches perfectly with human data by Daka et al. and a study Simó et al. In those two 2013 paper, the researchers state that type I diabetics (=low to no insulin) have very high, type II diabetics, on the other hand, very low SHBG levels (Daka. 2013), and that the inflammatory cytokine TNF-alpha and a hallmark feature of diabesity directly represses SHBG production, as well (Simó. 2013; check out the blue infobox below to get a "feeling" for further things that are related by one way or another to SHBG).

Increasing SHBG levels in the lower third of the normal range are nothing to worry about

SHBG does also figure (unsorted list; (+) = positive association meaning high SHBG high whatever, (-) = neg. association, meaning low SHBG high whatever) in ... Bone density (+) in male prostate cancer patients (Varsavsky. 2013) as well as US men in general (Trabert. 2013) || BMI, BP and HOMAR-IR (+) in postmenopausal women (Davis. 2013), in premenopausal women from the Japanese Saku cohort, the exact opposite was the case, i.e. high SHBG = low risk of type II diabetes (Gota. 2013) || breast cancer risk (-) based on data from the Nurses Health Study (Zhang. 2013) || prostate cancer (+ when abnormally high and testosterone low; García-Cruz. 2013) || weight loss after gastric bypass (+), obese women (Ernst. 2013) || peripheral artery disease (-) in older men and women (Maggio. 2013) || vascular dementia (-) in men (Xing . 2013)

In view of the results of previous studies which had a resistance training component, involved healthy, normalweight young (McCall. 1999), middle-aged (Cadore. 2008) or old individuals (Hakkinen. 2002) and had no effect on SHBG levels, it appears way more likely that increased insulin sensitivity in response to the resistance training lead to increases in SHBG and not vice-versa. This hypothesis would be supported by a rodentt study Roberts and his co-workers refer to in the conclusion of their paper:

"Selva et al. [Selva. 2007] elegantly demonstrated that elevated glucose (and fructose), rather than insulin might be the primary stimulus to lower SHBG. In this study, transgenic mice expressing different SHBG transgenes exposed to diets with elevated monosaccharides led to large decreases in SHBG." (Roberts. 2013)

This alone still does not suffice to shed more light on the SHBG <> diabesity connection, it should yet be enough to finally draw the curtain over the initially mentioned broscientific myth that SHBG was your enemy. As long as it's within the lower third of the normal range (which was the case in the study at hand) any further decrease is almost certainly going to have more negative than positive effects on your overall health - and if it impairs insulin sensitivity, your physique, as well (important note: both age and sex appear to modify the role of SHBG, for examples see in the infobox to the right)

Bottom line: Whether SHBG is an active modulator or passive indicator of efficient / inefficient glucose management has not been fully understood. It does yet appear to be more likely that changes in SHBG occur in response to changes in blood glucose. In any way, you certainly don't have to worry about the potential increase in SHBG in response to resistance training. Ah,... and in case you are wondering at least in obese postmenopausal women the same increases in SHBG occur in response to aerobic exercise, as well (Kim. 2013)

References:

• Cadore EL, Lhullier FL, Brentano MA, da Silva EM, Ambrosini MB, Spinelli R, Silva RF, Kruel LF. Hormonal responses to resistance exercise in long-term trained and untrained middle-aged men. J Strength Cond Res. 2008 Sep;22(5):1617-24.
• Daka B, Rosen T, Jansson PA, Råstam L, Larsson CA, U Lindblad. Inverse association between serum insulin and sex hormone-binding globulin in a population survey in Sweden Endocr Connect. 2013;1:129-133.
• Davis SR, Robinson PJ, Moufarege A, Bell RJ. The contribution of SHBG to the variation in HOMA-IR is not dependent on endogenous oestrogen or androgen levels in postmenopausal women. Clin Endocrinol (Oxf). 2013 Oct;77(4):541-7. 
• Ernst B, Wilms B, Thurnheer M, Schultes B. Reduced Circulating Androgen Levels After Gastric Bypass Surgery in Severely Obese Women. Obes Surg. 2013 Nov 29.
• García-Cruz E, Carrión Puig A, García-Larrosa A, Sallent A, Castañeda-Argáiz R, Piqueras M, Ribal MJ, Leibar-Tamayo A, Romero-Otero J, Alcaraz A. Higher sex hormone-binding globulin and lower bioavailable testosterone are related to prostate cancer detection on prostate biopsy. Scand J Urol. 2013 Nov 27.
• Goto A, Morita A, Goto M, Sasaki S, Miyachi M, Aiba N, Terauchi Y, Noda M, Watanabe S; the Saku Cohort Study Group. Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): a case control study. Cardiovasc Diabetol. 2013 Oct 16;11(1):130.
• Hakkinen K, Kraemer WJ, Pakarinen A, et al. Effects of heavy resistance/power training on maximal strength, muscle morphology, and hormonal response patterns in 60–75-year-old men and women. Can J Appl Physiol 2002;27:213–31.
• Kim JW, Kim DY. Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women. Metab Syndr Relat Disord. 2013 Dec;10(6):452-7.
• Maggio M, Cattabiani C, Lauretani F, Artoni A, Bandinelli S, Schiavi G, Vignali A, Volpi R, Ceresini G, Lippi G, Aloe R, De Vita F, Giallauria F, McDermott MM, Ferrucci L, Ceda GP. The relationship between sex hormones, sex hormone binding globulin and peripheral artery disease in older persons. Atherosclerosis. 2013 Dec;225(2):469-74.
• McCall GE, Byrnes WC, Fleck SJ, Dickinson A, Kraemer WJ. Acute and chronic hormonal responses to resistance training designed to promote muscle hypertrophy. Can J Appl Physiol. 1999 Feb;24(1):96-107.
• Roberts CK, Croymans DM, Aziz N, Butch AW, Lee CC. Resistance training increases SHBG in overweight/obese, young men. Metabolism. 2013 Jan 11.
• Selva DM, Hogeveen KN, Innis SM, Hammond GL. Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. J Clin Invest 2007;117:3979–87. 
• Simó R, Barbosa-Desongles A, Sáez-Lopez C, Lecube A, Hernandez C, Selva DM. Molecular Mechanism of TNFα-Induced Down-Regulation of SHBG Expression. Mol Endocrinol. 2013 Mar;26(3):438-46. 
• Trabert B, Graubard BI, Nyante SJ, Rifai N, Bradwin G, Platz EA, McQuillan GM, McGlynn KA. Relationship of sex steroid hormones with body size and with body composition measured by dual-energy X-ray absorptiometry in US men. Cancer Causes Control. 2013 Dec;23(12):1881-91.
• Varsavsky M, Reyes-García R, García-Martín A, Ramírez RG, Avilés-Perez MD, Muñoz-Torres M. SHBG levels are associated with bone loss and vertebral fractures in patients with prostate cancer. Osteoporos Int. 2013 May 16.
• Xing Y, Qin W, Li F, Jia XF, Jia J. Associations between sex hormones and cognitive and neuropsychiatric manifestations in vascular dementia (VaD). Arch Gerontol Geriatr. 2013 Jan-Feb;56(1):85-90.
• Zhang X, Tworoger SS, Eliassen AH, Hankinson SE. Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up. Breast Cancer Res Treat. 2013 Jan 3