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PCT: A Clinician’s View PART IV
Post-Cycle Pharmaceutics:
In Theory

- article first published on-line October 16, 2006

Dana Houser, MD, MHSA, CISSN

Author's Note: If you have yet to visit the PRIMER or PARTS I, II, III, and III½ of this series, please do so before proceeding.

Introduction

It isn’t hard to recall stepping into my first pharmacology class a few years ago. That’s right; my basic science program had officially transitioned! No longer would our studies include structure and function, but actual treatment.

Unfortunately, I was one of sixty-three other students that had survived microbiology and neuroscience (amongst others) simply graduating into a medical education that was merely updated with information provided by drug company representatives and journals funded by those same companies.

I became captivated, however, by the effect a chemical compound could have on bodily function. I found myself revisiting my biochemistry textbook and then outgrowing it, moving on to the purchase of copious others, too innumerable to count. I spent regular time (up to three or four hours per day) on Medline keeping up with current research [not an easy task with a concurrent medical education], leaving the door open to discuss and explore alternative methods of treatment with patients who want to choose this path as you have seen in previous parts of this series.

The last few attending physicians I have had the pleasure to work for have seen to it that I have my opportunity to voice these views and with it not only educate the patient, but also offer them new complementary modalities on the way to increased efficacy in patient care. Without further adieu, I give you therapeutic rationale to employing these techniques and the pharmacy that surrounds them as it applies to the post-cycle “patient.”

Wary is the Savvy Consumer

In PCT: ACV II, III, and III½, I have attempted to enlighten you on alternative modalities in the dietary supplement realm when embarking on post-cycle therapeutics. This should be done with the concurrent advice of a suitable [read: knowledgeable in the alternative therapeutic sense] health care professional, DESPITE very SLIM choices in this domain. That being said, I am often reminded of a story put out by one of the few I would call my greatest educators to date.

The setting was Thanksgiving in the year of (or surrounding) 1990 [author’s note: prior to DSHEA] of an FDA report centered on a man found dead in his car loaded with mugwart [Artemisia vulgaris], the Chinese and Native American ceremonial herb, as well as, European and Asian condiment and flavoring agent. It appeared that one of the flavoring phytochemical components, thujone, could, in exceedingly large doses, cause convulsions. Thujone was noted to be one of the main phytochemicals in absinthe, the addictive, brain-deteriorating alcoholic drink thought to have driven Vincent van Gogh mad.

The FDA responded as it does best with a cry for an immediate ban of mugwart. That is, until it learned that if the ban was upheld, it would have saw the potential end of similar thujone-containing compounds, most notably Sage [Salvia officinalis]. Sage was what would likely have been found as an even higher thujone-concentration per gram substance. At the same time, however, it found itself as an indispensable part of many person’s Thanksgiving turkey stuffing concoctions. When this latter connection was made, low and behold, the case and the imminent ban were dropped.

It is still not case reports such as these that leave me most concerned, but the number of people – namely in the bodybuilding community who have taken it upon themselves to self-prescribe for rationale that likely mimics our Part I domino. While we went on to show the potential of various compounds and the simple marketing that has won over the masses [Part II], much of it, as applied, simply does NOT pan out in practice [Parts III and III½].

Here, we are turning the page, however, to pharmaceutics – where, in the day and age where mail-order seems to reign supreme, the same rules apply. With copious years of touted research to support somehow greater safety records (as pharmaceutic reps may lead those of us in the allopathic domain to believe), some will boast comfort in this mentality – drug reps as clueless as certain supplement companies.

The media has recently offered a cry out to the consumer of the horror stories surrounding our beloved pharmaceutical agents sharing side effect profiles that match, if not surpass, many of our supplement analogues. This proved good for one reason only – it opened up mainstream to decades of scientific research that warned of these side effects long ago, yet few conventional doctors have listened. More recently, large scale studies, published in top medical journals have provided subsequent evidence that can no longer be ignored. This is a good example of how biased drug company research [which owns > 90% of the research surrounding particular compounds] can influence medical thinking and treatment for years before independent, non-drug company studies catch up with the truth. In the meantime, people become convinced that these drugs are safe.

Of course, pharmaceutical giants have tried to combat these adverse reports , but as mentioned above, when the media gets a hold of the news and offers word to mainstream – the crushing blow has already been delivered. Ephedra, prohormones, steroids anyone?

Pharmaceutical Politics – It begins with Semantics

A great example of the origin of political runs in pharmacy lies with synthetic progestins. Ever heard of a pharmaceutical company that references the term progestin to equal progesterone? What if I told you the two were neither synonymous NOR homologous terms? Interestingly enough, this misnomer has spilled over into the supplement industry – recent ads have suggested various PH/PS/AAS to be equivocal. I can’t entirely blame my misguided counters, however. Many physicians (thanks in part, to misinformation from many drug company reps) believe that synthetic progestins are merely different forms of progesterone. Uh hem, NONE of them is progesterone!

So, how is it that this incredible misnomer has seeped into the vocabulary of many drug reps with subsequent trickle-down in the domino-manner described in Part I to all the aforementioned individuals? The answer is likely found in a Journal of the American Medical Association (JAMA) study published in 2000 regarding a huge National Cancer Institute (NCI) study (C. Schairer, et al.) examining 46,000 women. It showed that conventional medical HRT using estrogen and synthetic progestins (most often Premarin, Provera, or Prempro) confers a higher risk of breast cancer than estrogen alone – in fact, read only the abstract as many simply have time for and this practice coupled with huge media attention yields shamefully misleading results because the term progesterone, with a pharm-rep push thereafter, was used to describe the progestins used in the study.

It wasn’t the first study to show increased risk of breast cancer, but it was the largest and with it came a higher reported statistical significance translated as “proof” to media and the layperson that the addition of progesterone [read: progestins] to combo pills exerted protective effects to the previously-discovered estrogenic sides. Now, despite how I have preached time and time again, that science NEVER “proves,” yet merely “supports” – this improper semantic usage doesn’t even remain my biggest concern here. It’s the loss of the concepts that dictate the current state of bodybuilding therapeutics. So without further adieu, we move on to those very concepts noting that…

A good grasp of the MAJOR concepts of post-cycle pharmacology is better than a poor grasp of ALL of the concepts of post-cycle pharmacology.

In fact, this statement can likely be applied to the entire field of pharmacology as a whole. And so we begin with estrogen.

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Estrogen in a NUTshell

Many steroidal and nonsteroidal compounds possess estrogenic activity. The most potent naturally occurring estrogen in humans, for both ER-alpha and ER-beta mediated actions, is 17-β Estradiol, followed by estrone and estriol. Each contains a phenolic A ring with a hydroxyl group at the carbon 3 position, and a beta-OH or ketone in the 17 position of the D ring.

Meet the Enemy



The adrenals and fat cells are the key estrogen epicenters/factories in the post-cycle male. As their production goes into high gear, unopposed (i.e. – provided HPTA shutdown with subsequent decreased testosterone), large amounts of estrogens have the potential of being secreted into your bloodstream and thus increasing your risk of deleterious side effects (i.e. – gynocomastia, et al.).

This entire process is a direct result of aromatization of the A ring. The reaction is catalyzed by a cytochrome P450 monooxygenase enzyme complex (aromatase or CYP19 - see later) that uses NADPH and molecular oxygen as cosubstrates.

Due to the hush nature imposed on the value of chemical means to alter body composition or aid human performance, there is an obvious lack of evaluation into the role of combating these potential side effects in athletes [i.e. – research]. We therefore, look to other areas where research is NOT frowned upon in times of estrogenic excess like breast cancer and osteoporosis.

Endocrine Therapy

Most endocrine therapies are believed to act on tumor growth (sorry guys, PCT wasn’t the first thing in mind in their creation) by reducing the synthesis of estrogen or by interfering with the action of estrogen at the level of the tumor cell. In addition, less well defined mechanisms of action include modulation of autocrine growth factors, direct cytotoxicity, apoptosis, and cell-cycle arrest. Surgical abalative procedures act directly or indirectly reducing the synthesis of estrogen in the ovary (for females) and adrenals (for males), whereas aromatase inhibitors interfere with the peripheral conversion of steroid precursors into estrogen. In contrast, antiestrogens act at the cellular level principally by interfering with the action of estrogen on the ER. The selective estrogen receptor downregulator fulvestrant downregulates the expression of the ER. The mechanism of action of additive endocrine therapies such as progestins, androgens, and estrogens remains poorly defined. While many choice sources would employ, adequate endocrine does NOT reside with a “perfect” set of agents for every cycle. The choice of endocrine therapy in PCT of a given patient is influenced by many factors: type of cycle run [i.e. – aromatizability, progestin vs. androgen, etc...], cycle length, AND previous endocrine therapy (including, but NOT limited to various cycles – i.e. – hypo/hyperthyroidism or use of such agents as Cytomel/Levothyroxine/Armour, etc, as well as diabetes or use of such agents as various oral hypoglycemics – most notably, metformin/glucophage, etc…) as outlined here.

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BASIC CONCEPTS DIGRESSION

Discussion of a couple basic concepts pertinent to pharmaceutics are necessary for the next two articles in this series – enzymes and phase metabolism. Please refer to the following article for more information if you have difficulty with either of the concepts described.

http://www.discountanabolics.com/for...ead.php?t=4906

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Hypogonadism

Back in part II, we discussed steroidogenic theory. Recalling from our discussion various feedback systems employed in such a thought process allows us to make predictions of where our defect lies. This usually is at the level of the feedback from the gonad to the hypothalamus and/or pituitary gland (i.e. – the HPTA, further broken down into HPLCA and HPSTA – see PCT: ACV Part II for more).

Hypogonadism can be localized to one of three different categories:
(1) HypERgonadotropic hypOgonadism
(2) HypOgonadotropic hypOgonadism
(3) EUgonadotropic hypOgonadism

Each of which we will take one by one and discuss how they may manifest in the post-cycle time frame.

HypERgonadotropic HypOgonadism (ER-O)

While this condition affects almost 50% of all patients with delayed puberty under normal circumstances, it accounts for less than 10% of all cases of hypogonadism in the post-cycle time frame. It includes conditions in which the gonads (the testes) are not functioning and are unable to respond to gonadotropins (LH, FSH); as a result, gonadotropin levels are high.

HypOgonadotropic HypOgonadism (O-O)

While this condition accounts for 10-15% of patients with pubertal delay under normal conditions, it actually constitutes the major rationale for hypogonadism in the post-cycle time frame (roughly 80-90%). The gonads are normal; however, the signal from the hypothalamus is not. Understand that this condition is not only influenced by the use of exogenous androgens, but also hypothalamic suppression by stress, improper dieting while in a hypermetabolic state, as well as multiple crossover feedback systems with other hormones.

EUgonadotropic HypOgonadism (EU-O)

Constitutional delay accounts for 10-20% of cases of hypogonadism under normal conditions, and is present in transient states in times of hypogonadotropic progression during the post-cycle time frame.


Hypogonadism, whatever the cause, is manifested through various clinical features of androgen deficiency (but more accurately depicted as unopposed estrogenic production) such as: Gynecomastia (likely the most feared of many post-cyclers), androgenic alopecia, and decreased libido. We will explore these clinical features (amongst others) one by one and discuss potential therapy which usually centers for the most part on anti-estrogen therapy as well as some additional palliative options.

Clinical Features of Post-Cycle Hypoandrogenism (Unopposed strogenization)

General

Lethargy, fatigue
Decreased Strength, Poor Concentration, Impaired Short-term memory, tendency to fall asleep
Deteriorating Work Performance
Headaches
Hot Flushes

Organ-Specific

Bone: osteopenia, osteoporosis
Muscle: sarcopenia (especially pectoral girdle)
Adipose: increase in fat mass
Breast: gynecomastia
Sexual/Reproductive

Decreased Libido
Erectile Dysfunction
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Gynecomastia

Oftentimes cited as the number one side effect of many post-cyclers, true gynecomastia (breast tissue – glandular or stromal in the adult male) is actually only experienced by a small subset of cycle runners. This is likely the effect of many cycles being run prematurely lending to an important clarification to be made between two subtypes of histologically-evident gynecomastia and lipomastia (more renowned as pseudogynecomastia).

True Gynecomastia
• Glandular Predominance 5-10%
• Stromal Predominance 30-50%

Pseudogynecomastia (Lipomastia)
• Adipose Predominance

The balance between stimulatory and inhibitory hormonal controls guide mammary development in the adult male. To illustrate how these controls work, we can look at this process as a balancing scale where tipped in one direction, growth of mammary tissue ensues; tipped in the other it is shut off. This all happens while being controlled by additional hormones (via crossover feedback systems) which aid in the over expression of one or the other.

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Sexual Dysfunction

The second most-feared complication though likely the least likely for concern at least in the potential long-term. Sexual dysfunction is a global term used to describe an array of separate misshapen effects observed almost uniformly associated with hypoadrogenic states. The spectrum of disorder suggested to span this heading includes:

- low libidinal
- decreased or anorgasmic states
- ejaculatory dysfunction (including volume and general ability)
- inability to attain / maintain penile erection (sorry ladies, suggested as the most common even during times other than post-cycle era).

In a landmark statement declared by the World Health Organization (WHO), the rather reserved organization recognized the important contribution of sexual health to men’s quality of life when it declared sexual health to be “a fundamental right of human beings.” Unfortunately, most men with sexual dysfunction are either undiagnosed or suboptimally treated. The usual estimation is that only 1 out of 10 even seek medical attention for this. The estimates could be even UNDERestimated in the post-cycle era with the rationale of many potential rationale including:

- cessation of cycle will bring libido, dysfunctional pattern back to norm
- not really a huge difference between pre-cycle sexual dysfunction patterns
- low desire to relay the use of AAS/PH/PS usage as potential etiology to health care practitioner

Libido defined

“Sexual urge, psychic energy comprising the positive loving instincts and manifested variously at different stages of personality development” as so eloquently defined by Webster’s New World Dictionary is what follows libido. The word libido is frequently used interchangeably with sexual desire although the actual meaning stems much deeper HOWEVER almost invariably centers on a lack of testosterone. While this may in fact be corrected by other modalities suggested throughout this article, the mere suggestion of hormonal therapies may not be enough.

This brings us to various pharmacologic support elements and cognitive behavioral therapy which usually center on adulteration of the penile erection. Something as simple as psychosexual counseling may be effective in its own right at complete correction of post-cycle erectile woes. Think of it this way: you go off a quoted “killer” cycle, your mood undoubtedly is subsequently seen to decrease secondary to body composition and/or subsequent strength woes and with it, welcome the potential for performance anxiety to accompany a decreased sense of well-being.

Of course, not everyone will benefit from such counseling and the agents most frequently discussed as everyone searches for the magic pill is a group of drugs called selective phosphodiesterase inhibitors. This is actually the result of how advanced such therapy has become as therapy used to incorporate penile implants, intrapenile injections of alprostadil, and intraurethral suppositories of alprostadil – none of which likely sound appealing to you at all, and rightfully so. Because of the increased efficacy, ease of use, and safety, the 3 phosphodiesterase inhibitors have gained broad-scale acceptance as first-line pharmaceutical therapy for men with erectile dysfunction.

Selective Phosphodiesterase Inhibitors

Representatives:
Sildenafil [VIAGRA]
Vardenafil [LEVITRA]
Tadalafil [CIALIS]

3 classes of enzymes – adenylyl cyclase, guanylyl cyclase, and phosphodiesterase – play a role in regulation of intracavernosal concentrations of cAMP and cGMP. Phosphodiesterases hydrolyze cAMP and cGMP, thus reducingtheir concentrations within the cavernosal smooth muscle. Although phosphodiesterase isoforms 2, 3, 4, and 5 are expressed in the penis, only phosphodiesterase 5 (PDE5) is specific to the nitric oxide (NO)/cGMP pathway in the corpora cavernosa.

Mechanism of Action: Relative selective inhibition of PDE5, blocking the hydrolysis of cGMP induced by NO, thus promoting cavernosal smooth muscle to relax.

Needless to say – our arrival at unopposed estrogen depends on many factors. For instance prerequisites likely include both a testosterone deficiency coupled with an estrogenic excess. How to address the side effects encountered are likely to be corrected only secondary to understanding the origin of the pathology. HPTA shutdown, androgen resistance, systemic dysfunction (unrelated to the cycle), and an excess of the aromatase enzyme all may play potential roles. Our initial step en route to correcting the pathology at hand lies with the excess side of the coin first tipping our scale back toward a more balanced setting. This is keeping in mind our desire to control our current state of hormonal disarray, with hopes of not overcompensating. How we approach this then begins with control of estrogen. We will review a comparative analysis of the studies done on these agents in the next part of this series employing a comparative analysis of our own.

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Anti-Estrogen Therapy

Many different systems of classification have been applied to this modality of therapy, but the most well-accepted is division into selective estrogen-receptor modulators (SERMs), selective estrogen-receptor downregulators (SERDs), and aromatase inhibitors (AIs).


SERMs

As discussed earlier, tamoxifen citrate is the lead compound of this class for reasons already stated. These agents bind to the estrogen receptor and exert EITHER estrogenic or antiestrogenic effects depending upon the specific organ. The recent decline in breast cancer mortality in Western countries is believed in part to be due to the widespread utilization of tamoxifen, however, as we have already explored the story is a little more complex than this. To summarize, in addition to its antagonistic effects on breast estrogen receptors, tamoxifen also exerts estrogenic effects in non-breast tissues, which influences the overall therapeutic index of the drug. What has resulted is the evolution of several novel anti-estrogen compounds (one of which, you have also been already introduced to above) that offer the potential for increased efficacy and reduced toxicity in comparison.

The SERM Class

A. Tamoxifen

B. Tamoxifen-Analogues[indent]1. toremifene
2. droloxifene
3. idoxifene

C. “Fixed-Ring” Compounds
1. raloxifene
2. lasofoxifene
3. arzoxifene
4. miproxifene
5. levormeloxifene
6. EM652

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SERDs

A group of compounds not often talked about in the bodybuilding world to date is the perhaps more effective Selective Estrogen Receptor Downregulators (SERDs), some of which are actually more appropriately termed “pure antiestrogens” versus the incomplete nature of the SERMs before them. Only one of five currently boasts FDA approval (hence number and letter connotation of B-E to follow).


The SERD Class

A. Fulvestrant
B. RU 58668
C. SR 16234
D. ZD 164384
E. ZK 191703

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AIs

Aromatase is the rate-limiting enzymatic product of the CYP19 gene family. CYP19 is uniquely assigned to the aromatase cytochrome P450 enzyme because it has little homology to other P450 enzymes. Aromatase is the rate-limiting enzyme responsible for the conversion of androstenedione and testosterone to the estrogens: estrone (E1) and estradiol (E2), respectively.

In whole, aromatase is an enzyme complex containing the cytochrome P450 hemoprotein and a flavaprotein, nicotinamide-adenine dinucleotide phosphate P450 reductase. The cytochrome P450 component catalyzes a series of 3 hydroxylation reactions of the androgen substrates described above.

CYP19 is highly expressed in human placenta and in granulosa cells of ovarian follicles, where its expression depends on cyclical gonadotropin stimulation. Aromatase is also present, at lower levels, in several nonglandular tissues, including: subcutaneous fat, liver, muscle, brain, normal breast, and breast cancer tissue.

Aromatase inhibitors (AIs) have two sites of potential action, one of which is important for our current discussion in males, the peripheral tissues. AIs can suppress most of the peripheral aromatase activity.










The AI Class

A. First Generation

1. Type 1
2. Type 2
a. Aminoglutethiamide (CYTADREN)

B. Second Generation

1. Type 1
a. Formestane (4-hydroxy-androstenedione; LENTARON)
2. Type 2
a. Fadrazole
b. Rogletimide (pyridoglutethimide)

C. Third Generation

1. Type 1
a. Exemestane (AROMASIN)
2. Type 2
a. Anastrazole (ARIMIDEX)
b. Letrozole (FEMARA)

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Select Pharmaceutics Theory

SERMs

Tamoxifen (Nolvadex)

Tamoxifen is without a doubt the most broadly used anti-estrogen therapy thanks to heavy marketing in the breast cancer campaigns. It was first synthesized in 1966 and initially developed as an oral contraceptive but was unfortunately found to INDUCE (rather than inhibit) ovuation, likely a side effect of its simultaneous anti- and pro-estrogenic activity. For four decades, tamoxifen has been studied and developed for use in various stages of breast cancer and most of the research we will explore in the next part of this article series actually centers on its most widespread use – palliative treatment of advanced breast cancer in postmenopausal women.

Mechanism of Action: Competitive partial agonist inhibition of estrogen binding to the estrogen receptor. There are 2 types of estrogen receptors (ER-α and ER-β), which have different tissue distributions and can either homodimerize or heterodimerize. Binding of estradiol and SERMs to the estrogen-binding sites of the ER’s initiates a series of events that includes alteration of the ER, dissociation of heat-shock proteins, and ER dimerization which facilitates the binding of the ER to specific estrogen-response elements (ERE’s) in the vicinity of estrogen-regulated genes. Many co-regulator genes interact with the receptor to act as co-responders or co-activators, while at least 50 transcriptional activating factors modulate the effects of estrogen on target genes. Differences in tissue distribution of ER subtypes, the function of co-regulator proteins, and the various transcriptional activating factors may explain the variable response of tamoxifen in different people and ER-positive tissues. Primary tissue types affected by tamoxifen (secondary to presence of ERs) include: breast, endometrium in women, the coagulation system (offering the potential for thromboembolism as a side effect of use), bone (modulation of bone mineral density, greater response from raloxifene), and liver (alteration of lipid profile).

Resistance: Associated with a decreased affinity for the receptor, a decreased number of receptors, or the presence of a dysfunctional receptor. It is not adequate to assume tamoxifen therapy will take care of post-cycle estrogenic woes for these stated reasons.

Pharmacokinetics: It is a non-steroidal agent effective on oral administration. It is partially metabolized by the liver through both N-demethylation and 4-hydroxylation. Tamoxifen’s 4-hydroxylation metabolite (4-hydroxytamoxifen) is intrinsically 100 times more potent and is predominantly created by cytochrome enzyme 2D6 metabolism of tamoxifen. Human liver microsome studies showed that N-demethylation of tamoxifen by cytochrome enzyme 3A4 produces a less potent anti-estrogen (N-desmethyltamoxifen).

Some metabolites, as suggested above, possess antagonistic activity, whereas others have agonistic activity. Unchanged drug and its metabolites are excreted predominantly through the bile into the feces.

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Toremifene (Fareston, aka - Chlorotamoxifen)

Easily thought of as tamoxifen with an attached chlorine molecule, toremifene is a triphenylethylene derivative which offers it a similar pharmacological profile. Recently, this agent has gained FDA approval in the treatment of metastatic breast cancer and with that came subsequent tickle-down favor in the eyes of many bodybuilders. Several phase II and randomized trials have compared toremifene with tamoxifen head-to-head of which we will address in the next part of this series.

The recommended daily dose is 60mg daily for metastatic purpose, however toremifene harbors roughly a 2:1 mg-for-mg dosing protocol for comparative effect. Toremifene and tamoxifen (provided adequate dosing) produce the same estrogen-like effects on the histology of the post-menopausal endometrium. How does this all translate into post-cycle dosing parameters? When we suggest 20mg as sufficient for post-cycle anti-estrogenic rationale of tamoxifen, this would leave us with a 40mg dosing as sufficient for this agent.

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Raloxifene (EVISTA)

We have already introduced raloxifene at other parts in this series. It is a newer SERM that acts in a manner similar to tamoxifen and other various SERMs. There are, however, some molecular differences worth noting here which contribute to various tissue level effects seen with this molecule. To illustrate the theoretic side of this argument, we will use a comparative analysis with the other prototypical SERMs – nolvadex and toremifene.



While perhaps a step up, we will review all available data comparing the various SERMs in the next part of this series which will likely help us pinpoint various administration techniques when employing such an agent for anti-estrogenic effects during PCT.

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SERDs

Fulvestrant (Faslodex)

Fulvestrant is the first FDA-approved agent (2002) of the new class of estrogen-receptor downregulators, which were hypothesized to have an improved safety profile, faster onset, and longer duration of action than the SERMs due to their pure ER antagonistic activity. It approved use is for post-menopausal women with hormone-receptor positive metastatic breast cancer that has progressed despite anti-estrogen therapy, but in the bodybuilding world – we know how long it seemingly doesn’t take before it finds its way into post-cycle regimes.

Mechanism of Action: SERDs, unlike mixed agonist/antagonist compounds such as tamoxifen and toremifene have a different molecular mode of action. This steroidal antiestrogen binds to the ER with an affinity that is said to be more than 100 times that of tamoxifen, at which point it causes destabilization of the ER dimer and enhanced ER degradation. This appears to occur due to fulvestrant’s long, bulky side-chain at the 7α position, which sterically hinders receptor dimerization, leading to increased ER turnover and disruption of nuclear localization. Unlike tamoxifen, which stabilizes or even increases ER expression, fulvestrant reduces the number of ER molecules in cells, both in vitro and in vivo.


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AIs

Aminoglutethimide (CYTADREN)

Aminoglutethimide [ah mee noe glue TETH ih mide] was the first aromatase inhibitor (Generation 1, type 2) originally developed as an anticonvulsant, to be subsequently identified for the treatment of metastatic breast cancer in postmenopausal women.

Mechanism of Action: Inhibition of both adrenal synthesis of pregnenolone (both an androgen precursor AS WELL AS estrogen) from cholesterol as well as extra-adrenal synthesis (read: peripheral conversion, for instance - subcutaneous fat). Because the drug also inhibits hydrocortisone synthesis, which evokes a compensatory rise in adrenocorticotropic hormone output sufficient to overwhelm the blockade of the adrenal, the drug is usually taken with hydrocortisone.


Anastrazole (ARIMIDEX) / Letrozole (FEMERA)

The imidazole aromatase inhibitors include:

• anastrazole [an AS troe zole]
• letrozole [LE troe zole]

and are nonsteroidal. They have gained favor for a number of reasons:

(1) they are more potent (96.8% aromatase inhibition vs. 89.3% aromatase inhibition for aminoglutethimide)
(2) more selective than aminoglutethimide
(3) they do NOT need to be supplemented with hydrocortisone
(4) they are devoid of androgenic side effects that occur with the steroidal AIs

Although they are considered second-line therapy in the post-cycle realm most often to Nolvadex therapy consideration would be warranted as first-line due to their almost total suppression of estrogen synthesis. A rate limiting factor remains their elimination through liver metabolism with C-17 alkylated agents. All these areas will be considered in the next part of this article series.

Mechanism of Action: Actions through anti-aromatic activity as previously described. The two prototypical third generation, type two nonsteroidal imidazoles phase I and phase II metabolism as well as dosing parameters which will be discussed in detail in the next part of this article series.


Exemestane (AROMASIN)

Mechanism of Action: More potent, orally administered analog of the natural substrate androstenedione that lowers estrogen levels more effectively than formestane. What is consistent with Type I vs. Type II AI discussions above, is the differentiating notes between this and the other two prototype third generation agents.

Third Generation / Type I - Exemestane: irreversible aromatase “suicide substrate”; steroidal

Third Generation / Type IIs - Anastrazole + Letrozole: reversible aromatase competitive inhibitors; non-steroidal

Recall, that due to exemestane’s steroidal structure, the potential for the compound to become androgenic is present, but NOT by the parent compound. It is EXTENSIVELY metabolized by the liver to inactive metabolites. Therefore, we block one enzymatic process and activate many others. A key metabolite, 17-hydroxyexemestane, which is formed by the reduction of the 17-oxo group via 17-beta-hydroxysteroid dehydrogenase, has weak androgenic activity, which actually likely contributes to its anticancer activity if you work out the reactions – at least on paper.

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Additional Anti- Estrogenic Agent

To round out our anti-estrogenic PCT categories, an additional agent worth mentioning employed and even oftentimes favored by many post-cyclers is clomiphene. Clomiphene shares similar effects on estrogen eradication with SERMs, yet differs from a structural standpoint, yielding both an alternative outcome as far as efficacy is concerned as well as side effect profile based on metabolic processing of the agent by the post-cycling male.

Clomiphene (CLOMID)

Structural Briefing: Clomiphene shares the triphenylethylene structure with tamoxifen and toermiphene, while raloxifene is a benzothiophene compound which we will see in our next discussion how this plays out in practice. We will also take a look via way of FSH stimulation how this compound stacks well with something like hCG (at least hypothetically) in various instances.

Another structural component to discuss is the issue of cis and trans isomerization. The trans isomers of clomiphene and tamoxifen have more antiestrogenic activity than do the cis isomers. This plays a role as tamoxifen tends to be marketed as ONLY the trans isomer, whereas clomiphene is available as the racemic mixture (mixture of both cis and trans isomers). I bring these last couple of structural facts up because this tends to increased the required daily dose of clomiphene compared to tamoxifen for the same efficacy.

Mechanism of Action: Clomiphene works as a weak estrogen agonist and a moderate estrogen antagonist. It is believed to act through antagonizing estrogen receptors in the HPTA (or HPTO in the female). By blocking estrogen’s negative feedback inhibition of gonadotropin secretion, clomiphene increases FSH and LH secretion and thereby induces ovulation in the female (a more accurate depiction of the drug’s intention) and spermatogenesis in the male (the latter of which will have an important role when combined with hCG – see later).

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Pro-Testosterone Therapy

One agent acts as the pharmaceutical prototype of this category – human chorionic gonadotropin (hCG).

Human chorionic gonadotropin (hCG)

Lutenizing hormone (LH) is a glycoprotein hormone consisting of two chains and, like FSH, is produced by gonadotroph cells in the anterior pituitary. LH is primarily responsible for regulation of gonadal steroidal hormone production. In men, LH acts on Leydig testicular cells to stimulate testosterone production. There is NO LH preparation presently available for clinical use – for this, hCG acts as a potential replacement. Recalling from earlier PCT:ACV articles and the discussion of the HPT axis, we pictorially look at this process below to help us illustrate where LH acts:




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Diagram Recap Summary: Gonadotropin-releasing hormone (GnRH) from hypothalamus controls the synthesis and release of gonadotropins (for our discussion here, I depicted LH in that position, however, keep in mind that the normal HPTA has FSH involved at the same site which will become pertinent to our discussion of spermatogenesis in PCT: ACV Part V). Gonadal steroid hormones (in our example, I have solely used Testosterone to exemplify our essential mechanism of action – however, keep in mind that things like estrogen as well as progesterone fit the bill in a bit more complex manner that is beyond the scope of this article) cause feedback inhibition (what you classically hear referenced as the “negative feedback” system) at the level of the pituitary gland on further LH secretion and the hypothalamus on further GnRH secretion – this has been depicted by negative signs in the diagram above. Inhibin is more pertinent to the discussion of the female hormonal status but plays a minor role here as well – I have depicted it solely for completion’s sake above.
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You may be more familiar with hCG’s use as the ideal hormone of choice during the early months of pregnancy derived from a particular part of the placenta that offers us a rather convenient means of detecting intra- or extra-uterine pregnancy amongst a couple of variable pathologic presentations (i.e. – choriocarcinoma, etc…). To many male peri- and post-cyclers, the more interesting note about hCG is that, with an almost identical structure to LH, it offers a suitable LH alternative to stimulate testicular testosterone production with effective virilization and in contrast to treatment with testosterone, also stimulates testisticular gowth.

For reasons of convenience, this is now administered subcutaneously, rather than intramuscular whereby we will see in the next part of this series there is no difference in efficacy. Despite its convenience, hCG does suffer some major drawbacks that we will explore in depth next time as well. There are huge dosing discrepancies suggested by the “experts” that may actually be what contributes to some of the deleterious potential of this agent.

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Testosterone’s More Potent Byproduct

Understanding the pathogenesis of androgenic alopecia and prostate health is quintessential to exploration of the agents typically employed in combating them. Recalling from PCT: ACV Parts II and III the various pathways of steroidogenic theory, it became evident that drugs that impact the enzymes en route to various metabolites of testosterone (namely in light of increased androgen while on cycle) 5-alpha reductase acts in production of the reduced and highly potent androgenic derivative, dihydrotestestosterone (DHT).





The two prototypical antagonistic molecules of this pathway were actually developed to treat benign prostatic hypertrophy (BPH), however, they have tended to gain more widespread usage in treatment of androgenic alopecia – both of which we will talk about in turn.

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Prostate Pathology

In PCT: ACV Part II, we discussed the history that surrounded this vestigle organ; in fact, we even hypothesized that it’s mere creation was for the sole purpose of presenting men with distress later in life. This usually manifests itself as either BPH or prostate cancer, the latter of which is the most common cancer in the adult male and the second most common cause of cancer death (the first is lung cancer) in the same populace. We talked about the potential use of a blood test (PSA) as guesstimates (albeit non-diagnostic) of prostate health. And we introduced the likes of saw palmetto, pygeum, and Boron. In PCT: ACV Part III, we expanded our supplemental talks and in PCT: ACV Part III and ½, we introduced the potential pitfalls with other agents in our fight against protecting this organ in more a preventative fashion.

Here, we will talk about the pathology that has gone a step further and advanced to the state of moderate to severe dysfunction. For this, we call upon various pharmaceutical agents to aid moderately severe symptoms due to obstruction of urinary tract outflow with hopes of staving off the potential for surgical intervention.

While the actual cause of BPH is undefined, several factors are known to be involved in the pathogenesis. These include age-related prostatic growth, prostatic capsule, androgenic hormones and their receptors, prostatic smooth muscle and adrenergic receptors, stromal-epithelial interactions and growth factors, and detrusor responses. Pharmacologic therapies target these various etiologic associations and we will address those here that are probably most affected by individuals who embark on exogenous cycles – namely hormonal regulation, adrenergic response of smooth muscle, and bladder outlet obstruction.

Hormonal Regulation of Prostatic Growth

Development of BPH requires testicular androgens as well as aging, however more recently there is perhaps a stronger association between estrogen and DHT than testosterone itself. There are several lines of evidence for this relationship.

(1) men who are castrated before puberty or who have disorders of impaired androgen production or action do NOT develop BPH.
(2) the prostate, unlike other androgen-dependent organs – maintains its ability to respond to androgens throughout life.
(3) androgens are required for normal cell differentiation in the prostate – they may also actively inhibit cell turnover and death.
(4) androgen deprivation (as is seen in the post cycle time frame) at various levels of the HPTA can reduce prostate size and improve obstructive symptoms.

While in the normal state of prostatic hyperplasia, the 4th item on this evidence list consists of: androgen ablation, antiandrogens, 5-alpha reductase inhibitors, and mixed-mechanisms (including progestins & cyproterone) – however, all but 5-alpha reductase inhibition are inapplicable due to the already low androgenic state of PCT.

While androgenic hormones are clearly required for the development of BPH, testosterone is NOT the major androgen in the prostate. Instead, 80-90% of prostatic testosterone is converted to the more active metabolite, DHT by the enzyme 5-alpha reductase (see above). Recently, two subtypes of 5-alpha reductase (conveniently type I and type II) have been described. Both type I and type II isoenzymes are found in the skin and liver, but only the type II isoenzyme is found in the urogenital tract. Drugs that block this enzyme can shrink the gland and alleviate urinary symptoms in men with BPH. We will defer addressing these items until the androgenic alopecia section that follows, a perhaps more pertinent use of these drugs in the peri- and post- cycle time frame.

Andrenergic Response of Prostatic Smooth Muscle Cells

Prostatic smooth muscle represents a significant proportion of the gland. Urethral elasticity and the degree of bladder outlet obstruction are undoubtedly influenced by the relative content of smooth muscle (cells at bladder neck + in prostatic capsule are richly populated with alpha-adrenergic receptors) within the prostate in males with BPH.

In the next part of this series, we will address studies designed to expand our therapeutic efficacy – and recent studies have suggested α1a to be the ones involved in prostatic smooth muscle contraction. These were actually formerly called α1c – but this nomenclature has since been adjusted. We will discuss clinical trials evaluating selective α1a antagonists such as tamulosin in PCT:ACV Part V.

Contractile protein gene expression in stromal smooth muscle cells is significantly altered after alpha blockade. This suggests that alpha-blocking agents may work not only by the simple relaxation of muscle tone, but also by affecting the phenotypic expression of contractile proteins in prostatic smooth muscle cells.

Alpha-blockers may also work by changing the balance between prostate cell growth and death. Some investigators hypothesize that BPH occurs as a result of a decrease in apoptosis (programmed cell death), allowing more cells to accumulate in the prostate, hence causing its enlargement. One alpha-blocker, doxazosin, has been shown to induce apoptosis in the stroma of the prostate.





The non-selective alpha-blocking agents described above (i.e. – phenoxybenzamine and phentolamine) while theoretically proving useful in the treatment of clinical signs and symptoms of stromal smooth muscle contraction, are rarely used for this purpose and more appropriately used in the pre-surgical management of the adrenal medulla tumor known as a pheochromocytoma.

Selective alpha-1-blockers as seen in the chart above (i.e. – Prazosin, Terazosin, Doxazosin, Alfuzosin) are also good agents to use in the treatment of hypertension and their selectivity as we will see in the next part of this article series actually contributes to a better side effect profile (namely, reflex tachycardia) as this receptor selectivity allows norepinephrine to exert unopposed negative feedback (mediated by presynaptic alpha-2-receptors) on its own release.

We will also address differences in drug half-lives as well as bioavailability and which ones may be of use in the post-cycle period within the next part of this series.

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HAIR GROWTH (Trichogenesis)

Hair growth is an interesting topic that holds extreme pertinence in the face of AAS/PH/PS users for various reasons. In males, androgenic alopecia (increased hair loss) becomes considerable issue with many individuals that run cycles. The converse is true with women, while running a cycle hirsuitism (increased hair growth in conspicuous places).

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We will digress for a moment and describe various types of hair seen in adults important for this discussion.

Vellus hair: soft, fine, unpigmented hair that covers apparently “hairless” areas of the body. Guys, for direct demonstration of this phenomenon, look very closely at your wife’s/girlfriend’s arms – yup, they actually are kind of hairy, huh?

Terminal hair: longer, course, pigmented hair that may grow in response to sex hormones (i.e. – over the chin and abdomen of men) or may be sex hormone-independent (i.e. – eyebrows and eyelashes).

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Hair growth, and thus hirsuitism, is regulated by:

(1) Number and Concentration of hair follicles. This varies according to racial and ethnic background but not gender. For example, Asian women generally have low concentrations of hair follicles, and hirsuitism is rarely seen in these individuals.
(2) Androgen Sensitivity of hair follicles
(3) Conversion Ability of vellus hairs to terminal hairs
(4) Degree of 5-alpha reductase activity in the skin, which determines local androgen activity.
(5) Ratio of growth to resting phases in affected hair follicles
(6) Thickness and degree to which individual hairs are pigmented

We will discuss both androgenic alopecia and hirsuitism in turn.

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Androgenic Alopecia

Omitted above in our prostate discussion were the 5-alpha reductase inhibitors, however, their application towards improvement of symptoms of BPH has been well studied and will be looked at thoroughly in the next part of this series. Recall from our earlier discussion the potential for both the presence of type I and type II 5-alpha reductase isoenzymes. This is important as finasteride imparts effects on solely the type II isoenzyme (see below), ensuring alleviation of not only the potential for male pattern baldness, but also prostatic symptoms (or more appropriately – urinary tract obstructive symptoms with prostatic overgrowth) as discussed above.

TRICHOGENIC AGENTS


Finasteride (PROSCAR, PROPECIA)

Mechanism of Action: 5-alpha reductase antagonist, type II > type I. This blocks the imperative step in DHT synthesis from testosterone


Dutasteride (AVODART)

Mechanism of Action: 5-alpha reductase antagonist, type I = type II. As above with Finasteride, this molecule works in the same way blocking testosterone conversion to DHT.


Minoxidil (topical – Rogaine)

Mechanism of Action: reverses the progressive miniaturization of terminal scalp hairs associated with androgenic alpopecia. Percutaneous absorption of minoxidil in normal scalp is minimal, but possible systemic effects on blood pressure can occur as this agent has concurrent vasodilatory properties (arterioles ONLY / NOT veins; through opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite). While this latter effect tends to be restricted to oral ingestion of this agent, it is plausible to occur with adequate absorption of the topical form.


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Hirsuitism

Hirsuitism is the presence of terminal hair in androgen-dependent sites where hair does not normally grow in women. These areas are located predominantly in the midline portions of the body, including:
- face
- chest
- abdomen
- inner thigh

Virilization is hirsuitism in the presence of signs & symptoms of hyperandrogenism, such as:
- increased muscle mass
- clitorimegaly
- temporal balding
- voice deepening
- increased libido

It can also be associated with signs & symptoms of defeminization, such as:
- decreased breast size
- loss of vaginal lubrication

While this tends to not be anything more than a cosmetic issue with cycling females, the presence of hirsuitism can be signs of another underlying androgenic precursor like an androgen-producing tumor. It is, therefore, important to treat this kind of thing immediately upon it showing up versus the “grin and bear it” mentality that many female cyclers partake in.

Diagnostic Evaluation

Serum testosterone levels tend to have less significance in the cycling female. Nine out of ten times, they are elevated unless the female had opted for a progestin-type agent in the first place. That being said, it is likely they wouldn’t be seeking evaluation if this were true.

Serum Testosterone: this is a non-specific marker of either ovarian or adrenal activity which tends to offer few clues. In the non-cycling female, total testosterone levels greater than 200 ng/dl would likely suggest an androgen-producing tumor. A profile that consists of increased free T, low total T, and hirsuitism would almost assure the cause to be a cycling female. However, further evaluation would still need to be undertaken in someone on cycle or in the immediate post-cycle period. This may include either a pelvic ultrasound for view of the ovaries and/or a CT or MRI for the best view of the adrenal glands.

Serum DHEAS: luxuriously enough, this is almost exclusively produced by the adrenal glands and reflects adrenal androgen activity. Levels greater than 700 μg/dl could potentially suggest an adrenal tumor and would likely warrant further exploration.

Serum Androstenedione: likely suggests ovarian disease.

Serum 3-alpha androstanediol glucuronide (3a-AG): The most underrated test in the peri-/post-cycling female. It is a peripheral tissue metabolite of DHT and actually could indicate target tissue cellular action. Increased levels indicate increased activity of 5-alpha reductase in the periphery.

Gonadotropins: useful with no explanation of the symptoms. An elevated LH:FSH ratio (2:1, though it can be less than this or even normal in 40% of cases) could be indicative of something like Polycystic Ovarian Syndrome (PCOS).

Serum 17-OHP + Cortisol: Not high on my list of what to order for someone with the potential for peri-/post-cycle hirsuiters.


Treatment

The most complete treatment is offered through a combination of hormonal suppression of hair growth and mechanical hair removal. The major goals remains arresting the virilizing process, however, NOT removing the hair. Once terminal hair has been established, simple withdrawal of androgens does NOT effect the newly established hair pattern. At all costs, it should be the goal of the peri-/post-cycling female to prevent the establishment of new hair follicles. Results, in turn, may NOT be apparent for 6-12 months after the cessation of the androgens indicating it is in effect a long-term process.


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ANTITRICHOGENIC AGENTS

Class I: Antiandrogens

(1) Combination oral contraceptives
(2) Medroxyprogesterone acetate: Suppresses gonadotropin (LH, FSH) secretion and subsequent androgen production
(3) GnRH agonists (Leuprolide, others)

Androgen-Receptor Blockers

(1) Spironolactone: concurrent aldosterone antagonist (thereby acting as diuretic) and 5-alpha reductase inhibitor
(2) Flutamide: nonsteroidal antiandrogen
(3) Cyproterone acetate: potent progestin and antiandrogen. Gonadotropin secretion inhibitor (primarily LH), which leads to decreased androgen levels

Class III: Others

(1) Finasteride: 5-alpha reductase inhibitor that blocks the conversion of testosterone to DHT (and subsequently androgenic side effects like hyertrichosis)
(2) Cimetidine: less potent androgen-receptor blocker
(3) Eflornithine HCl (VANIQA): a new topical cream that has proven rather interesting is an irreversible inhibitor of ornithine decarboxylase that catalyzes the rate-limiting step in the biosynthesis of polyamines. Polyamines are required for cell division and differentiation, and inhibition of ornithine decarboxylase affects the rate of hair growth.


Supportive Measures
- Shaving, tweezing, waxing, use of depilatories are TEMPORARY measures (as discussed above), which may need to be repeated daily. These methods neither stimulate hair growth NOR increase the rate of hair growth as you have likely heard the essential “wives tales” of hair coming in thicker, etc… if you opt to shave it, etc…
- Bleaching: effective for mild hair growth
- Electrolysis: permanent destruction of hair follicles. Multiple treatments are necessary, and scarring may in fact occur. This method should ONLY be used AFTER 6 MONTHS OF HORMONAL THERAPY when new hair growth has ceased.
- Laser Epilation: directed damage to hair follicles, which temporarily or permanently removes terminal hair. This method can be used over a larger area than electrolysis, but it is NOT yet perfected for the treatment of hirsuitism.