HGHup♂™

HGHUP♂ Promotes Radical Increases in Growth Hormone and Testosterone Production   HGHup♂ is so unique it falls into a new category altogether. HGHup is the world’s first hANh™ (Hybrid Anabolic / Near Hormonal); which is defined as a product that engages a synchronization of natural and exogenous factors to produce a pronounced anabolic and hormonal response. The distinct advantage of a hANh is that the user is able to obtain physiological benefits comparable to that of fully hormonal products while minimizing potential side effects and disruption of endogenous hormone levels post-usage.   HGHup♂ promotes greater increases in serum HGH and testosterone levels than any other product available without a prescription. It is the only orally viable compound that is proven to increase HGH and testosterone in human subjects.   USERS WILL EXPERIENCE: Average of 8% increase in lean muscle mass (in 6 weeks) Average of  25% reduction in body fat percentage (in 6 weeks) Increased strength via improved neural connectivity and increased lean muscle mass – add 20-40 lbs. on all major lifts! Faster healing of injuries and better recovery from physical stress and training Better skin tone – reverses premature aging Deeper, more restful sleep – feel better and more alert upon waking Increased fat metabolism

FAQ

Q: What is HGHup♂, and what does it do? A: HGHup♂ is an orally viable composition that: Increases the output of growth hormone and local IGF-1 levels Increases the duration/viability of growth hormone pulse mass Increases androgen receptor structure, function, and number Increases mean serum GH levels Increases testosterone levels Increases muscular strength and contractility Back to top  Q: When should I take HGHup♂ and how much should I take? A:In divided doses, two times per day, preferably on an empty stomach.  One dose should be in the AM, and one dose in the PM.  HGHup♂ can also be taken pre-workout for enhanced concentration, strength, and focus. Back to top Q: What are some of the benefits of taking HGHup♂? A: Some of the physique and sports-related benefits of the product are: Greater lean muscle mass Lowered body fat Very noticeable increases in strength Faster healing of injuries and better recovery from physical stress/training Better skin tone Deeper, more restful sleep Back to top Q: What are some good products to stack with HGHup♂ and are there any products I should avoid when taking HGHup♂?  A: HGHup♂ stacks well with just about anything in the Applied Nutriceuticals line, and it can be used in conjunction with hormonal products and will increase their anabolic effects, and it can be used along with other natural products for a big-time boost in strength and lean body mass gains. Note: We recommend that you avoid dosing HGHup♂ with a carbohydrate meal, as it may blunt the growth-hormone-releasing characteristics of the product.     Back to to Q: How long will it take to feel the positive benefits of HGHup♂™?   A:Strength-enhancement effects begin soon after the first dose, while physique-enhancing effects (lowered body fat and an increase in lean body mass) begin to become more apparent after the first week of usage. Back to top Q: Is HGHup♂ a prohormone?      A:No, HGHup♂ is not a prohormone, but has physique-enhancing effects similar to one; it falls in a category of products called “Near-Hormonals”, which are a group of substances that produce drug-like results, without drug-like side effects.    Back to top Q: Is HGHup♂ legal and is it IOC, MLB, NCAA, NFL, and NBA-compliant? A:Yes, HGHup♂ is completely legal, although one of our beta testers had this to say- “This is going to be huge...just really huge.  Bodybuilding, sports, anti-aging...you really have outdone yourself with this one.  My only concern is safety and the fact that the World Anti-doping folks are going to be on this like flies on stink when the word gets out.  If that happens, erase all your emails and disavow knowledge of me.”  He was kidding, but you get the message…  Back to top Q: I have heard that oral growth hormone supplements and herbal supplements do not work- why is HGHup♂ different from other herbal test boosters and GH supplements on the market? A:Because it does what the label claims, and does it well.   HGHup♂ is the result of 3 years of ongoing refinement to the formula with multiple rounds of testing to get it just right.  Growth hormone is a peptide hormone that is not orally viable if ingested, so in formulating HGHup♂ we had to go a different route in order make an oral growth hormone product that can boost GH levels comparable to that of injectable preparations. Every compound in the product is designed to work in concert with the other components, and no filler or ineffective components are found in this product.  HGHup♂  also utilizes components that boost androgen levels, increase the number and function of androgen receptors, and create an overall BETTER anabolic environment in which levels of testosterone and GH are optimized,  leading to better recovery, increased lean body mass, and lower body fat. Back to top Q: Has there been any scientific research done on the constituents of HGHup♂? A: Definitely. The components in HGHup♂ have voluminous research studies supporting their effectiveness, with documented benefits including (but not limited to) increased mean serum GH, increased muscular strength, testosterone enhancement, and anti-catabolism. For the sake of continuity, only the doses and standardizations used in research studies are used in the product, period, and journal references are sited at the conclusion of the HGHup♂ technical write-up, which can be found at www.appnut.com Back to top Q: Is it ok to use HGHup♂ for long periods of time, or should I cycle it? A: It seems to be well-tolerated, even during longer (2-3 month) dosing cycles.     Back to top Q: Who shouldn’t take HGHup?? A: Anyone under the age of 18, those who take MAOI’s or are on any other type of prescription medications, and if you are pregnant or nursing. Always check with your doctor before beginning any supplementation regimen.  Back to top

HGHup♂™ TECHNICAL INFORMATION

 

PRODUCT DESCRIPTION:

 

HGHup♂ is so unique it falls into a new category altogether. HGHup♂ is the world’s first hANh™ (Hybrid Anabolic / Near Hormonal); which is defined as a product that engages a synchronization of natural and exogenous factors to produce a pronounced anabolic and hormonal response. The distinct advantage of a hANh is that the user is able to obtain maximal physiological benefits comparable to that of fully hormonal products while minimizing potential side effects and disruption of endogenous factors post-usage.

 

HGHup♂ promotes radical increases in serum HGH and testosterone levels without a prescription. It is the only orally viable compound that is proven to increase HGH AND testosterone in human subjects.

 

PRODUCT CHARACTERISTICS:

• Increases the output of growth hormone and local IGF-1 levels
• Increases the duration/viability of growth hormone pulse mass
• Increases androgen receptor structure, function, and number
• Increases natural production of testosterone

 

Figure 1: HUMAN GROWTH HORMONE AMINO ACID SEQUENCE

 

EFFECTS RELATED TO PHYSIQUE AND LIFE ENHANCEMENT:

• Greater lean muscle mass
• Lowered body fat
• Increased strength
• Faster healing of injuries and better recovery from physical stress/training
• Better skin tone
• Deeper, more restful sleep

 

Figure 2: AMINO ACID SEQUENCE OF SOMATOSTATIN, Ghrelin, AND GHRH

 

MAIN MECHANISMS OF ACTION:

 

Mucuna Pruriens, Vitamin B6 and L-Dopa: Increase Growth Hormone Output and Testosterone Production While Concurrently Decreasing Somatostatin and Prolactin.

• HGHup♂ contains highly concentrated L-Dopa derived from Mucuna Pruriens.  Mucuna Pruriens is an Ayurvedic Herb that has both anti-hypoglycemic and L-Dopa-increasing qualities. (32). L-Dopa has been shown to significantly increase levels of growth hormone in human subjects when administered orally. (1, 2, 3, 33).
• Oral viability in HGHUP♂ critical for product effectiveness, as growth hormone cannot be absorbed and is rendered ineffective due to the fragility of the ingredients. Several good examples are synthetic growth hormone (see Fig. 1) and growth hormone releasing hormone (GHRH, see Fig. 2).  These compounds cannot be administered orally; because of their fragile amino acid sequence is destroyed by stomach acids. This also holds true with the vast majority of the so-called “GH Boosters” and “Peptides” commonly found in sports nutrition products.
• L-Dopa and Dopamine have also been shown to inhibit prolactin, a hormone that suppresses male testosterone production. Prolactin also has a positive correlation with a second hormone called somatostatin, which decreases the both amount and effectiveness of circulating growth hormone. Therefore, by lowering prolactin (and consequently somatostatin) levels, HGHUP♂ increases both testosterone and GH production; leading to greater recovery and lean body mass (38, 39).
• Vitamin B6 is also included in the formula for HGHUP♂, as it can also help further lower prolactin levels and increase the night-time peak of GH release pulse, while at the same time increasing the rise in GH associated with exercise by as much as 23% (7).

Huperzine-A: Increasing AChE Inhibition and Mean serum GH by Decreasing Somatostatin

• Huperzine-A is a strong acetylcholine esterase (AChE) inhibitor.  Acetylcholine esterase inhibitors have been shown in numerous scientific studies to inhibit somatostatin via a variety of synergistic biomechanisms; all of which contribute to increased levels of growth hormone (9, 10, 11, 12, 13, 14, 15, 16, 17, 18).
• Somatostatin is a hormone that exerts effects on anterior pituitary as well as pancreatic, liver and gastrointestinal function (40, 41, 42, 43) .

• Somatostatin is of extreme importance because it directly effects growth hormone release and is the major regulating factor in slowing or even stopping growth hormone output.
• Therefore, by inhibiting somatostatin, overall mean serum GH will increase (41, 42).
• Somatostatin inhibits GH secretion indirectly via antagonizing GHRH secretion (41, 42, 43).

• Consequently, the Huperzine-A, in HGHUP♂ increases the length, intensity, duration of growth hormone pulses and increases mean serum GH levels, therefore allowing for more of the positive anabolic and anti-aging benefits associated with GH.(8, 10, 12-17, 19-20).   

 

FIGURE 3: POTENCY OF ACETYLCHOLINE ESTERASE INHIBITORS

 

Green Tea Extract, and (−)-epigallocatechin-3-O-gallate (EGCG): Increasing Dopa Decarboxylase Inhibition and the AChE-inhibiting Effects of HGHUP♂

 

• Dopamine crosses the blood/brain barrier poorly, and cannot exert optimal effects on target receptors unless enough of the compound reaches the brain.  L-Dopa is freely absorbed across this barrier, and when L-dopa crosses the barrier readily, growth hormone levels increase.  (1-6, 32-33)
• L-Dopa is most effective when conversion of L-Dopa to dopamine is mediated by a decarboxylase inhibitor.  A decarboxylase inhibitor is a substrate that inhibits the metabolism of one biological entity into another biological entity  (2, 3, 4, 5, 19, 20, 37).
• A decarboxylase inhibitor is generally administered at the same time as L-Dopa / Mucuna in order to reduce conversion of the L-dopa into dopamine in the periphery.  (−)-epigallocatechin-3-O-gallate (EGCG), which is found in high amounts in the green tea extract used in HGHUP♂, is a potent decarboxylase inhibitor.  The decarboxylase-inhibiting qualities of EGCG have been documented in several recent studies, in that EGCG seems to prevent L-dopa from converting into dopamine; allowing more significant levels of L-dopa to reach the brain and increase growth hormone levels (1, 2, 3, 4, 5, 37).
• EGCG has also been shown to significantly increase the effects of Huperzine A on acetylcholine esterase inhibition by increasing the transport of Huperzine-A by serum albumin.  This allows for greater amounts of acetylcholine to be present, therefore allowing for greater mean serum growth hormone. Increased serum GH from HGHUP♂ allows for increased anabolism, better recovery, and increased muscle mass (19, 20).

 

HGHUP♂ INCREASES ANDROGEN RECEPTOR QUANTITY AND DENSITY AND CREATES A BETTER BINDING ENVIRONMENT FOR EXISTING ANDROGENS

L-Carnitine-L-Tartrate and Magnesium: Increasing Androgen Receptor Number and Density, and the Creation of a Better Binding Environment

• L-Carnitine L-Tartrate is an amino acid that has been shown to increase the number of androgen receptors in skeletal muscle, creating a better binding environment for testosterone and other androgens by allowing for a greater number of intact receptors available for hormonal interactions. (21-23)
• Magnesium has been shown in more recent studies to inhibit the binding of steroid hormone binding globulin (SHBG) and free testosterone.  SHBG binds free testosterone and allows it to be excreted from the body, without binding the androgen receptor.  Magnesium keeps this from happening by altering the binding affinity of testosterone to SHBG; thereby allowing for increased amounts of free testosterone to remain active in the bloodstream. (24)
• Other human research has shown that supplemental magnesium, when taken along with other ingredients like DHEA and Zinc, can significantly increase free testosterone. (25-27)
• Therefore, HGHUP♂ allows for greater numbers of androgen receptors and a better binding environment for testosterone in skeletal muscle. This is a new breakthrough in sports supplementation as HGHUP♂ creates a better target for circulating free testosterone, allowing for greater binding of testosterone to the extra receptors which leads to increased protein synthesis, better recovery, and increased muscle mass.

 

HGHUP♂ INCREASES TESTOSTERONE

Mucuna Pruriens, Selenium, and Chlorophytum Borivillanum Ethanolic/Sapogenic Extract: Increasing Testosterone Levels

• Mucuna Pruriens has been shown in several recent human studies to improve testosterone levels and spermatogenesis in animal studies and humans, via prolactin inhibition. Prolactin, as mentioned earlier, is a hormone that suppresses male testosterone production (30-31, 34-36, 38-39).
• The ethanolic and sapogenic extracts of Chlorophytum Borivaillanum have also been shown in animal studies to increase testosterone, and anecdotal data from products containing this compound also point to increased testosterone and lean body mass for users of this phyto-androgenic compound. However, the mechanism of action of Chlorophytum is poorly understood. (28- 29)

Figure 4: Chlorophytum Study Data

• Selenium has been shown in several studies to have direct effects on the biosynthesis pathways of testosterone.  Selenium is rate-limiting in testosterone production in men, and if enough selenium (selenium deficiency is very common) is not available, testosterone will not be produced in optimal levels (27).

 

Administration, Timing, and Dosing

• Normal GH pulses (see chart below) occur throughout the day.  For a normal male in an average day, there are 10 pulses of GH secretion lasting on average 96.4 mins with 128 mins between each pulse. The largest GH pulse occurs during stages 3 and 4 of the sleep cycle.  GH pulses during sleep (see Fig. 5) occur at nearly triple the rate of GH pulses during the day (44-45)
• Somatostatin release is controlled in large part by the cholinergic system.  The cholinergic system is responsible for regulating the amount of acetylcholine found in the body at any given time. Acetylcholine is a neurotransmitter responsible for muscular activation in the peripheral nervous system, and tends to be excitatory in the central nervous system  (CNS) (10, 11, 12, 13).  
•  The CNS component of acetylcholine mediates the cholinergic system, and this is important because the cholinergic system is responsible for mediating growth hormone response (11, 12, 13, 14, 15).
• The mechanism through which this is accomplished is simple: by increasing acetylcholine levels, there will be an increase in mean serum GH.   HGHUP♂ increases acetylcholine via lowering levels of acetylcholine esterase or AChE (an enzyme that breaks down acetylcholine) (11, 12, 13, 14, 15).    
• Taking an acetylcholine esterase inhibitor (in the case of  HGHUP♂, Huperzine-A) before sleep will result in dramatically reduced somatostatin levels and dramatically increase serum GH levels (1-4, 5, 9-17,19, 20, 44, 45). 
• Somatostatin seems to be the major inhibitory factor in sleep-related GH pulses.  When AChE is inhibited by pryridostigmine (an AChE inhibitor very similar to Huperzine-A) GH pulse mass is increased, and mean serum GH almost doubled.  In terms of potency, Huperzine-A has actually been shown to be more potent than pyridostigmine bromide in terms of AChE inhibition (9-17, 19-20) .  
• There has also been a very popular trend recently of bodybuilders taking Huperzine-A along with injectible synthetic growth hormone, because the compound is so effective at inhibiting somatostatin and increasing serum GH (46)
• Taking  (−)-epigallocatechin-3-O-gallate (EGCG) along with Huperzine-A will increase Hup-A’s effectiveness in inhibiting acetylcholine esterase, and its ability to allow the cholinergic system to suppress somatostatin.  This has been verified in several scientific studies (19-20).

 

Figure 5: The Pulsatility of GH in Humans

 

Figure 6: Theoretical Pulsatility of GH after taking HGH-UP♂

• Taking a supplement containing L-Dopa with a decarboxylase inhibitor before sleep can allow for dramatically increased levels of GH (1-5, 32- 33, 37-39).
• Hypoglycemia (low blood sugar) can also increase the amount of GH released.  Insulin and GH are antagonistic, and the lower the insulin level, the higher the GH level (see chart below, 44-45).

Figure 7:  GH Response to Lowered Blood Sugar

• Timing of the dose and manipulating insulin levels before sleep is the key getting great results with HGHUP♂  (44-45, 47)
• Best results occur when a 4-6 capsule dosage is taken on an empty stomach (fasted state) 30 minutes before bedtime (44-45, 47)

Why Most OTC GH Products Are Ineffective, and How HGHUP♂ Differs

• Over the last 20 years, a variety of products that claim to boost HGH orally have been promoted in the US sports supplement market.  The vast majority of these products have been completely ineffective for several reasons:

• Growth hormone is a peptide (a long chain amino acid structure), that cannot be taken in an oral form, due to the destruction of the sequence by the acidic environment of the stomach.  Any supplement containing “oral growth hormone” is a scam (47).
• Many products use a combination of amino acids such as arginine and lysine in “kitchen sink” formulas, and claim that their combination is “scientifically proven” to work.  Many amino acids boost growth hormone levels, but most of the time, it is only when taken intravenously, or in completely unattainable dosages that would make a normal person extremely sick.  And the correct dosage is in gram amounts, not in the milligram range offered in many of these products (47).
• Even if these products allow for a viable release of GH, there is nothing present to inhibit somatostatin, which has been found to be the biggest factor in controlling GH levels (47)
• Many of these products are powdered mixes that contain sugar, sweeteners, or other compounds that may increase blood sugar.  As discussed above, this will render the product virtually useless due to the inverse relationship between glucose and growth hormone (47).
• HGHUP♂ differs from these compounds because of the nature of the formulation.  Every compound in the product is designed to work in concert with the other components; no filler or ineffective components are found in this product (47).
• HGHUP♂ utilizes the latest research on compounds which have been overlooked by other companies. The secret of the product is in the complexity, effectiveness and synergism of the blend (1-47). 
• HGHUP♂ is the first product to positively manipulate somatostatin; this alone puts it in a class by itself.
• HGHUP♂  also utilizes components that boost androgen levels, increase the number and function of androgen receptors, and create an overall BETTER anabolic environment in which levels of testosterone and GH are optimized,  leading to better recovery, increased lean body mass, and lower body fat (1-47).

 

Stacks and Tips to Maximize the Product

• Take Bio-Mend Anti-Oxidant formula
• High ORAC Value
• Protects cellular membrane
• Protects transcriptional factors (mRNA and DNA)

• In general, maintain a healthy diet and lifestyle:

• Drink Plenty of water; at least 64 oz. per day
• Ingest at least 1 gram of protein per lb. of body weight daily
• Sleep at least 7 hours per night
• Eat lots of fruits and vegetables
• Eat lots of complex carbs
• Eat 5-6 smaller protein and carb-rich meals throughout the day
• Increase calories to at least 500 Kcal/day over your normal intake
• BCAAs and Creatine will be helpful
• Avoid alcohol and tobacco
• Take HGHUP♂ on an empty stomach before going to sleep, or take it with an all-protein meal.  Remember, carbohydrates/insulin decrease the effectiveness of the product.
• HGHUP♂ can be stacked with synthetic growth hormone and will make it more effective

In conclusion, HGHUP♂ in the most effective orally administered HGH and Testosterone agonist yet to be offered in the history of sports nutrition. For more information, you can contact Applied Nutriceuticals at info@appliednutriceuticals.com.

Studies and Clinical Info

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2. Schönberger W, Grimm W, Ziegler R. The effect of nacom (L-dopa and L-carbidopa) on growth hormone secretion in 75 patients with short stature. Eur J Pediatr. 1977 Dec 30;127(1):15-9.
3. Schönberger W, Ziegler R, Brodt B, Grimm W. HGH secretion after oral application of L-dopa and L-carbidopa. Eur J Pediatr. 1976 Jun 8;122(3):195-200.
4. Fevang FO, Stoa RF, Thorsen T, Aarskog D. The Effect of L-dopa with and without decarboxylase inhibitor on growth hormone secretion in children with short stature. Acta Paediatr Scand. 1977 Jan; 66(1):81-84
5. Philippi H, Pohlenz J, Grimm W, Koffler T, Schönberger W. Simultaneous stimulation of growth hormone, adrenocorticotropin, and cortisol with L-dopa, carbidopa, and propranolol in children of short stature. Acta Paediatr, 2000 Apr;89(4):442-446.
6. Gordon M, Markham J, Hartlein JM, Koller JM, Loftin S, Black KJ. Intravenous levodopa administration in humans based on a two-compartment kinetic model. J. Neurosci Methods, 2007 Jan 30:159(2):300-307. Epub 2006 Aug 24
7. Pyridoxine (B6) suppresses the rise in prolactin and increases the rise in growth hormone induced by exercise. 1982 Aug 12;307(7):444-5.
8. Barletta C, Sellini M, Bartoli A, Bigi C, Buzzetti R, Giovannini C Influence of administration of pyridoxine on circadian rhythm of plasma ACTH, cortisol prolactin and somatotropin in normal subjects. Boll Soc Ital Biol Sper. 1984 Feb 28;60(2):273-8
9. Gordon RK, Haigh JR, Garcia GE, Feaster SR, Riel MA, Lenz DE, Aisen PS, Doctor BP. Oral administration of pyridostigmine bromide and huperzine A protects human whole blood cholinesterases from ex vivo exposure to soman. Chem Biol Interact. 2005 Dec 15;157-158:239-46. Epub 2005 Oct 26.
10.  Wang R, Yan H, Tang XC. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin. 2006 Jan;27(1):1-26
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13.  Giustina A, Bossoni S, Bodini C, Doga M, Girelli A, Buffoli MG, Schettino M, Wehrenberg WB. The role of cholinergic tone in modulating the growth hormone response to growth hormone-releasing hormone in normal man. Metabolism. 1991 May;40(5):519-23
14. Friend K, Iranmanesh A, Login IS, Veldhuis JD Pyridostigmine treatment selectively amplifies the mass of GH secreted per burst without altering GH burst frequency, half-life, basal GH secretion or the orderliness of GH release. Eur J Endocrinol. 1997 Oct;137(4):377-86
15.  Dinan TG, O'Keane V, Thakore J. Pyridostigmine induced growth hormone release in mania: focus on the cholinergic/somatostatin system. Clin Endocrinol (Oxf). 1994 Jan;40(1):93-6
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18.  Haigh JR, Johnston SR, Peppernay A, Mattern PJ, Garcia GE, Doctor BP, Gordon RK, Aisen PS. Protection of red blood cell acetylcholinesterase by oral huperzine A against ex vivo soman exposure: next generation prophylaxis and sequestering of acetylcholinesterase over butyrylcholinesterase. Chem Biol Interact. 2008 Sep 25;175(1-3):380-6.
19.  Xiao J, Chen X, Zhang L, Talbot SG, Li GC, Xu M. Investigation of the mechanism of enhanced effect of EGCG on huperzine A's inhibition of acetylcholinesterase activity in rats by a multispectroscopic method.  J Agric Food Chem. 2008 Feb. 13:56(3) 910-915.
20.  Zhang L, Cao H, Wen J, Xu M. Green tea polyphenol (-)-epigallocatechin-3-gallate enhances the inhibitory effect of huperzine A on acetylcholinesterase by increasing the affinity with serum albumin.
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25.  Excoffon L, Guillaume YC, Woronoff-Lemsi MC, André C. Magnesium effect on testosterone-SHBG association studied by a novel molecular chromatography approach. J Pharm Biomed An. 2009 Feb. 20: 49(2). 175-180.
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30.  Saxena S and Dixit V.K: Role of total alkaloids of Mucuna pruriens Baker in spermatogenesis in male rats, Indian Journal of Natural Products. 1987, 3(2), 3-7.

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33. Tharakan B, Dhanasekaran M, Mize-Berge J, Manyam BV. Anti-Parkinson botanical Mucuna pruriens prevents levodopa induced plasmid and genomic DNA damage.Phytother Res. 2007 Dec;21(12):1124-6.
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Effect of Mucuna pruriens on semen profile and biochemical parameters in seminal plasma of infertile men. Fertil Steril. 2008 Sep;90(3):627-35. Epub 2007 Nov 14.

35.  Shukla KK, Mahdi AA, Ahmad MK, Shankhwar SN, Rajender S, Jaiswar SP. Mucuna pruriens improves male fertility by its action on the hypothalamus-pituitary-gonadal axis. Fertil Steril. 2008 Oct 28. [Epub ahead of print]
36. Shukla KK, Mahdi AA, Ahmad MK, Jaiswar SP, Shankwar SN, Tiwari SC .Mucuna pruriens Reduces Stress and Improves the Quality of Semen in Infertile Men .Evid Based Complement Alternat Med. 2007 Dec 18. [Epub ahead of print
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