Estrogen, Prolactin, Testosterone, and Pathophysiology of ED and Libido

[SacToSD]

Please contribute research with proper references and links, and/or experiences related to the hormones involved in erectile dysfunction and low libido.

Notes on Testosterone and ED/Libido:

Although the role of androgens in erectile function in men is controversial, primary or secondary hypogonadism is considered key in the pathophysiology of erectile dysfunction (ED) (Korenman et al, 1990; Aversa et al, 2004; Yassin and Saad, 2007). Androgens exert not only genomic effects, for example, by stimulating the expression of the neuronal isoform of nitric oxide (NO) synthase (Reilly et al, 1997; Park et al, 1999), but also nongenomic effects, for example, by relaxing the smooth musculature of coronary arteries and the aorta (Yue et al, 1995; Deenadayalu et al, 2001).

J Androl 2008;29:514–523



T is important for modulating the central and peripheral regulation of ED. Erectile function depends on a normal penile anatomy and a functioning venoocclusive mechanism, which implies integrity of the
structural and cellular components. It was demonstrated that T deprivation causes apoptosis of cells from cavernosal and spongiosal tissues, which can be prevented by androgen administration (Podlasek et al, 2005).

J Androl 2008;29:514–523



Smooth muscle, a vital component of the penile anatomy, is a critical structure for tumescence. Using a rat model, investigators established that experimental castration caused significant reduction in trabecular smooth muscle and a significant increase in connective tissue deposition concomitant with loss of erectile function, indicating that T is vital for smooth muscle integrity (Traish et al, 2003). Further support for the androgenic requirement for penile erection derives from scientific knowledge of the molecular basis for NO function in the penis. It was shown that the NO pathway plays a critical role in initiation and maintenance of erectile function (Burnett, 2004). In animals, the expression of NO synthase (NOS) isoforms in the Canguven and Burnett N 5 a-reductase Inhibitors on Erection 515 corpus cavernosum is regulated by androgens. Researchers found that NOS activity is decreased in
erectile tissues of castrated animals, as is the erectile response to pelvic nerve stimulation (Lugg et al, 1995; Park et al, 1999; Baba et al, 2000). These investigators further established that T restores the erectile response and normalizes NOS protein expression and activity. On the whole, the mechanism of penile erection is a function of corporal smooth muscle relaxation required for blood filling and engorgement of the penis in response to sexual excitement, exerted at the molecular level by cGMP by way of its effector cGKI (Andersson, 2001). Type 5 phosphodiesterase enzyme (PDE5), the predominant phosphodiesterase expressed in the corpus cavernosum, has regulatory control of penile vasorelaxant actions. In the animal model, castration resulted in reduced protein expression and activity of PDE5, although androgen treatment up-regulated the expression of PDE5 activity (Morelli et al, 2004). In addition, the efficacy of PDE5 inhibitors to elicit erections induced by electrostimulation of the cavernous nerves following castration was decreased. After castrated animals were treated with T, the tissue relaxation caused by PDE5 inhibitors was successfully restored (Traish et al, 1999; Morelli et al, 2004). Clinical studies also indicate the direct influence of androgens on erectile responses to PDE5 inhibitors. Investigators carrying out clinical trials in androgen deficient men confirmed these observations and found that with androgen substitution these men displayed enhanced responses to the ED treatment (Aversa et al, 2004; Shabsigh et al, 2004; Morelli et al, 2007). These studies strongly suggest that T exerts vital physiological actions in erectile function.

J Androl 2008;29:514–523



The data suggested that DHT is the active androgen that prevents erectile failure in castrated rats.
With recent discoveries of PDE5 inhibitors as well NOS signaling in the penis, Park et al (1999) examined whether DHT influences the erectile response and the mRNA expressions of NOS isoforms in the penile corpus cavernosum of castrated rats. For this purpose, rats were separated into 5 groups: sham, castrated alone, and castrated receiving T, DHT, or T with the 5ARI finasteride. Both T and DHT effectively restored the erectile response to normal. NOS activity and the amount of neuronal NOS (nNOS) mRNA were also reduced in castrated rats but restored by both T and DHT replacement.

J Androl 2008;29:514–523



On the other hand, T is more relevant than DHT in erectile function, which requires central and peripheral androgenic activity. T exerts both humoral endocrine and local paracrine effects. It is likely that androgens are vital for the development, maintenance and function of penile tissue and regulation of erectile physiology. However, the critical androgenic substance for these effects is most likely T rather than DHT.

J Androl 2008;29:514–523
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Notes on Prolactin and ED/Libido:

Hyperprolactinemia induces hypogonadism by interfering with the secretion of gonadotropinreleasing
hormone (GnRH) from the hypothalamus (Figure 2).4,5 The resulting decrease in serum T is believed
to be the cause of the erectile dysfunction, although there may be an end-organ effect of prolactin on
the penis.4 Surprisingly, not everyone with hyperprolactinemia has a low serum T level or complains of erectile dysfunction.6,7 However, when the serum prolactin is corrected in patients with an elevated prolactin level and a low serum T level, the serum T level usually returns to a normal value, and erectile function is usually restored (if erectile dysfunction was present).2 Simply treating the patient with exogenous T does not usually correct the erectile dysfunction (unless the prolactin levels are returned to normal). Hyperprolactinemia is a very rare cause of impotence in a general population
of men with impotence.8 However, men who have hyperprolactinemia have a high incidence of
sexual dysfunction, and the erectile dysfunction appears more likely to resolve in patients with the most
severe hyperprolactinemia once this glandular disorder is corrected.7

Main Points
• The prolactin level should be measured in men presenting with a complaint of
erectile dysfunction who have a low serum testosterone level.
• Hypogonadism is almost always the cause of an endocrinopathy that affects
erectile function.
• In hyperprolactinemia, which induces hypogonadism, the excess prolactin
interferes with secretion of gonadotropin-releasing hormone, resulting in
decreased testosterone and erectile dysfunction.
• Hyperprolactinemia caused by a pituitary tumor can be managed with surgery
and/or a dopamine agonist.

Hyperprolactinemia and Erectile Dysfunction
Scott I. Zeitlin, MD, Jacob Rajfer, MD
University of California, Los Angeles, School of Medicine

http://www.ncbi.nlm.nih.gov/pmc/arti...02001_0039.pdf

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Notes on High Estradiol and ED/Libido:

Results of this investigation indicate that oestradiol causes pathophysiological changes in erectile function. These observations provide an indirect evidence for the possible sexual health hazards in man upon inadvertent exposure to environmental oestrogens, ageing and derangement of E2–T ratio.

International Journal of Impotence Research (2003) 15, 38–43. doi:10.1038/sj.ijir.3900945

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Bonus Feature: Trenbolone and It's Systemic Effects

1. Adrenal Gland
Trenbolone has been implicated in shrinking the adrenal gland in vivo, and antiglucocorticoid activity via inhinbition of dexamethasone-induced transcriptional activity.

The adrenal cortex is regulated by neuroendocrine hormones secreted by the pituitary gland and hypothalamus ? Adrenal insufficiency can also occur when the hypothalamus or the pituitary gland, both located at the base of the skull, does not make adequate amounts of the hormones that assist in regulating adrenal function. This is called secondary adrenal insufficiency and is caused by lack of production of ACTH in the pituitary or lack of CRH in the hypothalamus.

2. Androgen Receptors, Progesterone Receptors
Trenbolone shows strong binding to the androgen receptor, to the progestin receptor and to the glucocorticoid receptor (21). Concerning the androgenic activity, it can be assumed that trenbolone acts like other androgens - in comparison with the most active endogenous hormone dihydrotestosterone (RBA= 100) the affinity of trenbolone-17P is even higher (RBA= 109).

“Biochemistry and physiology of anabolic hormones used for improvement of meat production” Review article, Heinrich Meyer

3. Pituitary, Hypothalamus, Testis

Since trenbolone possesses both estrogenic (ER) or progestogenic (PR) activity, it inhibits LH & FSH by directly down-regulating the GnRH receptors on the pituitary, while also reducing GnRH release from the hypothalamus. Therefore, progestin based AAS such as trenbolone (and nandralone) are “double suppressive” because they are binding to the AR and PR and suppressing LH & FSH by two different mechanisms.

Patterns of LH secretion in castrated bulls during intravenous infusion of androgenic and estrogenic steroids: Pituitary response to exogenous luteinizing hormone-releasing hormone
M.J. D’occhio et al. Biology of reproduction 26, 249-257 (1982)

Studies on the role of sex steroids in the feedback control of FSH concentrations in men.
Sherins RJ, Loriaux DL. 1973 J Clin Endocrinol Metab. 36:886-893

So, What Does This Mean?

1. In terms of Erectile Dysfunction
"On the other hand, T is more relevant than DHT in erectile function, which requires central and peripheral androgenic activity. T exerts both humoral endocrine and local paracrine effects. It is likely that androgens are vital for the development, maintenance and function of penile tissue and regulation of erectile physiology. However, the critical androgenic substance for these effects is most likely T rather than DHT." J Androl 2008;29:514–523

This implies that trenbolone affects and/or displaces testosterone and DHT from androgen receptors, thereby effecting erections.

Further, the increases in prolactin seen on -- and after cessation of -- trenbolone have an adverse, inhibitory effect on testosterone and LH levels. High prolactin is correlated with low libido and erectile dysfunction.

 

[SacToSD]

Results of this investigation indicate that oestradiol causes pathophysiological changes in erectile function. These observations provide an indirect evidence for the possible sexual health hazards in man upon inadvertent exposure to environmental oestrogens, ageing and derangement of E2–T ratio.

International Journal of Impotence Research (2003) 15, 38–43. doi:10.1038/sj.ijir.3900945
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In summary, administration of a potent and selective aromatase antagonist reduces estradiol and
elevates mean LH concentrations equivalently in young and older men. The low estrogen-feedback
state in elderly men unmasks diminished incremental LH pulse amplitude and area; absence of further
acceleration of LH pulse frequency; impaired regulation of the orderliness of LH release; and reduced
testosterone to SHBG ratios. Thus, aging alters expected hypothalamopituitary-gonadal adaptations
to short-term partial estrogen depletion in healthy men.

J Clin Endocrinol Metab. 2005 January ; 90(1): 211–218.

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In summary, administration of a selective aromatase antagonist lowers (24-h mean)
concentrations of estradiol by 50% and elevates LH concentrations by 100% in young and
older healthy men. Negative-feedback adaptations to partial estrogen withdrawal differ
significantly by age. In particular, relative estrogen depletion in older, unlike young, men fails
to evoke (further) augmentation of the following: 1) incremental LH peak amplitude and LH
pulse area; 2) daily LH pulse frequency; 3) LH secretory-pattern irregularity; and 4) the molar
ratio of testosterone to SHBG concentrations. These outcomes extend concepts of agingassociated
regulatory defects in the male by hypothalmopituitary gonadal axis to include
estrogen-dependent feedback control.

J Clin Endocrinol Metab. 2005 January ; 90(1): 211–218.
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Results of this investigation indicate that oestradiol causes pathophysiological changes in erectile function. These observations provide an indirect evidence for the possible sexual health hazards in man upon inadvertent exposure to environmental oestrogens, ageing and derangement of E2–T ratio.

International Journal of Impotence Research (2003) 15, 38–43. doi:10.1038/sj.ijir.3900945
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Similar pathophysiological imbalance between androgen and oestrogen is likely to be associated with other clinical states of adult-onset hypogonadism9 as well as hyperoestrogenism.10 Under such circumstances, since E2 is a more potent gonadotropin suppressant than testosterone,4 a vicious cycle that leads to an absolute testosterone deficiency is likely to be precipitated by E2-induced decrements in LH and FSH release.

International Journal of Impotence Research (2003) 15, 38–43. doi:10.1038/sj.ijir.3900945
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Conforming to structural changes in the cavernosum of trans-sexuals exposed to oestrogen,17 the penile morphology demonstrated a reduction in smooth muscle and relative increase in connective
tissue distribution.

International Journal of Impotence Research (2003) 15, 38–43. doi:10.1038/sj.ijir.3900945

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(a) Light micrograph 1: trichrome-stained light micrograph of control rat cavernosum. Scattered sinusoids, smooth muscle fibres and connective tissue show normal architecture (magnification: 50). (b) Light micrograph 2: trichrome-stained light micrograph of cavernosum from E2-(0.01 mg) treated rat at 12 weeks. Some degree of connective tissue proliferation is seen (magnification: 50).
(c) Light micrograph 3: trichrome-stained light micrograph of cavernosum from E2-(0.1 mg) treated rat at 12 weeks. There is extensive loose connective tissue proliferation amidst the distribution of sinusoidal spaces and scanty smooth musculature (magnification: 50).

International Journal of Impotence Research (2003) 15, 38–43. doi:10.1038/sj.ijir.3900945
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1) Smooth Muscle Dysfunction.*Researchers now know that testosterone both maintains smooth muscle and the nerves the fire them in the corpus cavernosum. [1][5] For example, researchers have noted that in castrated animals, the nerve fibers and myelin sheaths around them actually shrink and "wither". And they have also noted that smooth muscle content in the corpus cavernosum decreased as well. [2] Yes, testosterone affects everything in a male!
2) Corpus Cavernosum Integrity. The research points to the fact that low testosterone can actually affect the connective tissue within the corpus cavernosum.* While you are losing smooth muscle, you are also likely gaining more connective tissue, i.e. collagen. [1][2][5] The ECM (extracellelular matrix) changes for the worse, another structure implicated in erectile dysfunction. [6]* This is a sort of "hardening" similar to what causes problems throughout your body. You need for the corpus cavernosum to be flexible and expandable in order to properly compress the outflow.
The bottom line is that researchers have found that in a low testosterone environment, the inside of the penis literally atrophies and is replaced with inelastic, fibrous tissue.*
For some of you that have discovered that you lived in a hypogonadal state for years without knowing it, this may be a scary prospect.* "Did it do permanent damage?" is the natural question to ask yourself.
The answer is probably 'yes' to some degree.* However, the good news is that studies show that if testosterone is restored, normal erectile function usually goes with it.* This means that the damage could not have been too severe from a long term low testosterone environment and indicates that a significant reversal is possible.*
By the way, some of you who may not respond well to PDE5 Inhibitors, such as Viagra or Cialis, may find that restoring your testosterone restores your erections for the above reasons. One study looked at hypogonadal males who did not respond to Viagra and found a significant restoration of erectile function after HRT (Testosterone Therarpy). [3] Very similar results were found in a study of Cialis non-responders as well. [5] In other words, sometimes the problem is nitric oxide and sometimes it is low testosterone (or both).
So the bottom line is that many of you need to either Increase Your Testosterone Naturally or discuss with your doctor Hormone Replacement Therapy if you want your erections back.* And, yes, Sex is Good For You.
* REFERENCES:
1) J Sex Med, 2005, 2:759–770, "The Physiological Role of Androgens in Penile Erection: Regulation of Corpus Cavernosum Structure and Function"
2) Endocrinology, Apr 1 1999, 140(4)1861-1868, "Effects of Castration and Androgen Replacement on Erectile Function in a Rabbit Model"
3) J Urol, 2004 Aug, 172(2):658-63, "Randomized study of testosterone gel as adjunctive therapy to sildena?l in hypogonadal men with erectile dysfunction who do not respond to sildena?l alone"
4) Grape seed
5) Andrologia, 2006, 38:61–68, "Testosterone and erectile function in hypogonadal men unresponsive to tadala?l: results from an open-label uncontrolled study"*
6) Braz. J. Morphol. Sci., 2008, 25(1-4):35-10, "Stereological study of extracellular matrix of penile body in felis domestica: experimental model applied to erectile dysfunction"

http://www.peaktestosterone.com/Venous_Leakage.aspx (Venous Leakage)

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Androgens are deemed to be critical for the development, growth, and maintenance of penile tissue as well as for erectile function. Androgens are also reported to inhibit differentiation of stroma progenitor cells into adipocytes and promote differentiation into smooth muscle. The objective of this study was to investigate whether androgen deprivation results in accumulation of adipocytes in the corpus cavernosum. Mature, New Zealand white male rabbits were subjected to sham surgery (control) or orchiectomy. Two weeks after surgery, erectile function was assessed by monitoring changes in intracavernosal blood pressure (ICP) in response to pelvic nerve stimulation. All ICP measurements were normalized to the mean systemic arterial blood pressure. In parallel studies, penile cross sections from control and orchiectomized rabbits were fixed and stained with either Masson's trichrome or hematoxylin and eosin to assess smooth muscle and connective tissue content. Alternatively, tissue sections were stained with Toluidine blue to assess accumulation of fat-containing cells. Orchiectomy resulted in loss of erectile function and penile atrophy, associated with reduced trabecular smooth muscle and increased connective tissue content. Most strikingly, tissue from orchiectomized animals exhibited accumulation of fat-containing cells (adipocytes) in the subtunical region of the corpus cavernosum. We hypothesize that androgen deprivation promotes differentiation of progenitor stroma cells into an adipogenic lineage producing fat-containing cells, thus altering erectile function.

Journal of Andrology, Vol. 26, No. 2, March/April 2005

 

[Michael Scally MD]

Central Nervous System Agents and Erectile Dysfunction

Cortical regions act as centers for integration of sensory stimuli and hormonal influences to initiate sexual desire and libido. These stimuli and hormones then act through sympathetic and parasympathetic pathways to control the peripheral activities that result in a penile erection. These cortical pathways explain the occurrence of erections without genital stimulation such as those occurring during fantasy, visual stimuli, and sleep.

Whereas the role of nitric oxide (NO) as an end effector has been well established, the role of the central nervous system (CNS) in mediating penile erections remains unclear despite several laboratory and animal studies attesting to its importance. Initial studies were based on animal models with retrograde labeling of pathways, but more recent reports have used newer techniques such as the positron emission tomographic scan.

Among a large variety of areas that may potentially be involved within the cortex, the medial preoptic area and the paraventricular nucleus (PVN) of the hypothalamus along with the hippocampus seem to be the principal areas of interest. The PVN contains dopaminergic neurons whose stimulation is associated with penile erection. Whereas injection of dopaminergic agents in this region potentiates erections, lesions in this region result in a loss of erectile ability.

In further attempts to characterize the role of the PVN in erectile functioning, researchers recorded potentials from individual neurons in the PVN as well as local field potential activity in anesthetized rats during erectile activity. Apomorphine in erectogenic doses was injected peripherally and resulted in variable firing patterns of the neurons in the preerectile and erectile phases.

The melanocortinergic system also has multiple sites of action within this complex network. This system consists of neuropeptides such as adrenocorticotropic hormone, b-endorphin, and a, b and g melanocyte-stimulating hormones (MSHs) apart from their receptors and various antagonists. The melanocortins are posttranslational products of the prohormone pro-opiomelanocortin (POMC), which produces 8 different peptides based on the site of cleavage. POMC messenger RNA exists in several human tissues including the genitourinary tract.

Among the various melanocortin receptors (MCRs), MCR3 and MCR4 have been found in the hypothalamus and MCR4 primarily has been seen to be involved in modulating sexual function. The CNS administration of a-MSH induces penile erections and yawning, somewhat similar to that seen with apomorphine. Mizusawa and colleagues implanted catheters in the lateral cerebral ventricle or the subarachnoid space in 78 male Sprague-Dawley rats and injected a-MSH. These injections resulted in penile erections and an increase in intracavernosal pressure, which was abolished by the administration of NO inhibitors. Similar responses were produced by intracerebroventricular oxytocin, but intrathecal a-MSH did not produce any erectile response, suggesting a central role for a-MSH.

Centrally acting agents are not among the currently recommended treatments for erectile dysfunction (ED) in the guidelines of the American Urological Association and the European Association of Urology. These guidelines recommend phosphodiesterase 5 inhibitors (PDE5i) sildenafil, tadalafil, and vardenafil as first-line therapies with options including prostaglandin E1, intracavernosal vasoactive agents, vacuum constriction devices, and penile prosthesis. The guidelines recommended switching from an oral to an alternate therapy among nonresponders.

PDE5i have a significant failure rate, including both primary and secondary failures among patients who may have initially responded to therapy. Further, some patient groups, such as in those after radical prostatectomy, have poorer outcomes with PDE5i. Adverse effects, time to onset of action, and lack of spontaneity are additional concerns with these agents. The current guidelines leave little oral options for these men, and there is clearly a potential for the development of alternative therapies. The principal reason for the recommendation against centrally acting agents is the lack of adequate scientific data on their efficacy and safety. This article reviews the centrally acting agents and the data on their efficacy.

Functional neuroanatomy of penile erection.

The various biochemical pathways modulating hypothalamic control of penile erection and sexual behavior. Serotonin facilitates penile responses through 5-hydroxytryptamine receptor (5-HT1C) and inhibits sexual behavior through 5-HT1A. Excitatory amino acids, N-methyl-D-aspartate and L-aspartate; GABA, g-aminobutyric acid; GHRP, growth hormone–releasing peptide; NA, noradrenaline (a1-adrenergic receptor produces stimulation and inhibits sexual behavior); NO, nitric oxide.


Kumar R, Nehra A. Central nervous system agents and erectile dysfunction. Urol Clin North Am 2011;38(2):165-73. Central nervous system agents and erectile dysfunc... [Urol Clin North Am. 2011] - PubMed result

Several centrally acting agents have shown potential to improve erectile function in men with ED. They still lack adequate data in efficacy and tolerability. Nasal formulations of apomorphine and bremelanotide seem to be the most likely candidates for future approval. They may play a role, specifically in men who fail phosphodiesterase 5 (PDE5) therapy, are unable to take PDE5 inhibitors because of side effects, or are on nitrate therapy. This article reviews the centrally acting agents and the data on their efficacy.