Sex hormone health considerations

Written by

Justin Gregory Maguire

Table of contents

  1. Cholesterol: A decisive factor in gross health.
  2. Pregnenolone: What is your foundation looking like?
  3. Progesterone: Are you wired yet tired, stressful capacity consideration.
  4. Glucocorticoid and mineralocorticoid reactions: With great power comes great depletion.
  5. Androstenedione: A mindful androgen.
  6. Considerations and conclusions: Putting it all together.

Sex Hormone pathways

The use of anabolic steroids has become wide spread and common within the fitness community.  From bodybuilding to sports performance, augmentation of one’s physiology is becoming a staple in many ‘health’ strategies. Increased understanding is needed in the affect exogenous hormone use may have within one’s complete biology. Thus the purpose of this (very brief) manual is to educate those intended on using anabolic steroids of both the performance impact as well as homeostatic disruption.


Most believe there are two or even three types of cholesterol (HDL, LDL and even VLDL), however this common misperception is not accurate. There is but one type of cholesterol with different carriers, each impacting the affect cholesterol may have on human physiology.

Cholesterol contains 27 organic carbon molecules that can be found in either esterified or un-esterified forms. Only un-esterified cholesterol can be absorbed through the gut, thus majority (75 %) of our cholesterol is produced endogenously (within the human body) and not gained through diet as many have been lead to believe. Cholesterol is necessary for recovery, thus cases whereby elevated cholesterol levels are found could possibly indicate stress within the body, in which endogenous production has been increased to contend with healing.

As cholesterol is a hydrophobic molecule, required carriers are needed to facilitate its transport and this is where we note different lipoproteins. Transport proteins are called Apo proteins, once they are bound to cholesterol these proteins become Apo lipoproteins and the vehicle carrying the cholesterol itself is called a lipoprotein. Apo lipoproteins hold the the lipoprotein together and come in many different shapes, most notably are Apo A1 and Apo B. Apo A1 is bound to HDL (high density lipoproteins), whereas Apo B is often associated to LDL (low density lipoproteins) and VLDL (very low density lipoproteins) carriers. The ratio between Apo A1 and Apo B is an accurate measure to determine the influence cholesterol may have on physiology.

HDL and LDL, why is either good or bad?

The media has often taught us that LDL cholesterol is bad. The press, however, is remiss in its understanding of the role LDL has within the periphery. LDL increases transport of lipids and cholesterol to peripheral tissue for purpose of energy production and turnover. The rate and length in which this occurs will have either a positive or negative impact on inflammation and subsequent arterial health. HDL is seen as a ‘good’ cholesterol as it re-directs cholesterol deposited in the periphery back to the liver for further metabolism. In essence, both HDL and LDL are vital for one’s metabolism. In particular, mitochondrial health is affected. Thus, rather being deemed bad or good, one should consider balance in ratio. Suppression of cholesterol (under 160mg/dl) may actually lead to oxidative stress which may result in:

  1. Poor cellular membrane health
  2. Myelin sheath formation (conductivity between neuron cell bodies)
  3. Steroid hormone synthesis
  4. Endogenous synthesis of vitamin D (sunlight is not the only contributing factor to consider)
  5. Bile salts (fat emulsification and phase bile bound conjugated toxin removal)
  6. The immune system (cytokine reactions)
  7. Repair and wound healing

*Thus, its not about lowering cholesterol, but rather improving ratio and overall particle interaction throughout the body.

Ratios to consider

Apo B: Apo A1 ratio:


Male = < 0.29

Female = < 0.25

Above average risk

Male = > 1.3

Female = > 1.0

Total Cholesterol/HDL ratio


Optimal = 0-3

Exogenous use of androgens disrupts cholesterol synthesis in two major outcomes:

  1. Suppression of HDL formation
  2. Proliferation of LDL and total cholesterol production

Suppression of HDL formation is noted due the role HDL plays within ongoing sex hormone production. Below is a depiction of human sex hormone production:

When there is an increased perception of hormone concentration noted through thalamic interaction subsequent synaptic reaction is halted in order to aid re-establishing homeostatic norms of androgens throughout the body. As HDL is primarily responsible for delivering cholesterol to tissues (gonads, ovaries, adrenals) for purpose of androgen formation, shutting down HDL production will inevitably occur. Reducing HDL concentration impairs regulation of cholesterol synthesis between the periphery and hepatic tissue, thus resulting in potential cytokine expression and probable immune suppression/dysregulation .

Proliferation of both LDL and total cholesterol are seen in supra-physiological hormonal environments. As with an increase of androgens, there is also a subsequent increase of mitochondrial activity and overall beta oxidation. In methods to contend with the demand, the body initially ramps up cholesterol production and redirects LDL carriers to the periphery, This provides a highly demanding system to initiate the necessary raw material it could need to maintain a new homeostatic ‘norm.’ Over time, however, total cholesterol production may be suppressed resulting in immune compromise and probable auto-immune disease.


Produced predominantly by the adrenal glands (zona reticularis), pregnenolone is the outcome of cholesterol synthesis along the pathway(s) of sex hormone production. Often cited as a precursor hormone, pregnenolone provides the raw material in the formation of these main hormones:

  1. Progesterone
  2. Testosterone
  3. Glucocorticoids and mineralocorticoids
  4. Estrogen

Regulate by the anterior pituitary function, position of the autonomic nervous system plays a contributing role toward optimal pregnenolone production and neuro-protective function. As pregnenolone is able to cross the blood brain barrier, its role in myelin sheeth formation is noted. Position of available cholesterol thus plays a massive role in pregnenolone production and function.

Balance between neurotransmitters is vital for psychological and physiological health. GABA (Gamma aminobutyric acid) plays a massive role in both mood regulation (aids dopamine receptor sensitivity) and gastric endocrine reaction (contributes to the release of Motilin). Pregnenonlone activates Gaba-chloride channels thus not only aiding improved mood and digestion but overall ability to sleep.

Exogenous steroid use often exacerbates the need of pregnenolone stores in promotion of glucocorticoid production. As supra-physiological concentration of androgens excites sympathetic control centers, increased adrenal output is often noted. Thus base hormone pregnenolone is heavily depleted during administration of excessive exogenous hormone use.


Synthesised from pregnenolone in which conversion takes place in two steps. Progesterone can be thought of a modulator hormone in which levels may predetermine conversion reactions throughout the sex hormone production pathway.

Neurologically progesterone plays a major role in the production of DHEA which is a powerful neuro-androgen, responsible for protecting the brain from oxidative damage through mediating increased astrocyte formation aiding the resilience of the blood brain barrier against pathogens or chemicals. In addition to aiding production of DHEA, progesterone also induced Gaba-chloride channel activity thus lowering potential of excitotoxicity in the brain.

Pregnenolone aids modulation of 5 alpha reductase activity which limits the conversion of testosterone into DHT (Dihydrotestosterone). Excessive DHT has been associated with the following conditions:

  1. Male pattern baldness
  2. Prostate growth

Estrogenic activity is often proliferated during exogenous hormone use, as biochemical reactions try to re-establish homeostatic balance. Pregnenolone concentration directly opposes unopposed estrogens from expression receptor activity and subsequent physiological changes.

Balance between progesterone and estrogen increases potential of:

  1. Feminization (gynecomastia)
  2. Cardiovascular inflammation
  3. Insulin insensitivity and poor glucose disposal
  4. Hepatic health compromise (impaired detoxification)
  5. Cholesterol metabolism
  6. Overall fat metabolism

Increase of exogenous hormone use suppresses progesterone production due to depleted pregnenolone availability, this in turn further aggravates the central nervous system into a distorted perception of stress, as pregnenolone acts as precursor and modulator or cortisol production and overall modulation. Thus impact on the autonomic tone is grossly shifted with the use of (excessive) exogenous hormone supplementation due to potential it may have in progesterone suppression.

Glucocorticoids and mineralocorticoids

Mediated through the activity of the anterior pituitary in response to stress, cortisol along with aldosterone are primarily produced over all other sex hormones in the pursuit of preserving life. The metabolite reactions required for cortisol are far less in number than those expressed in testosterone production, thus exhausted stress stimuli eventually leads base hormone pregnenolone into a deficit, influencing potential of androgen production and neuro androgen protection.

Cortisol is of major concern when dealing with exogenous androgen hormone use as metabolic flexibility is altered to contend with a higher perceived basal turnover rate by inducing increased caloric expenditure. As most are aware steroids may aid glycogen retention and protein turn over of hypertrophied tissue, establishing such turnover requires reactions of both anabolic and catabolic nature to ensure apoptosis occurs in prevention of carcinogenic cell growth.

Thus environments of high androgens stimulate control centers in the brain, within components found in the telencephalon to aggravate ACTH (adrenocorticotropic hormone) release, resulting in elevated concentration of cortisol. Over time, environments of high androgens will exhaust adrenal cortex reactions, thus lowering overall cortisol production, leading to adrenal fatigue. In addition to reduced cortisol function, reactions of mineral control (cardiovascular heatlh) and neuro-protective (nervous system regulation) androgen production are all negatively influenced in states of adrenal fatigue.

Anabolic use should consider monitoring and regulation of one’s autonomic state and metabolic flexibility. Shift toward a predominantly sympathetic position will only impair potential of cross energy metabolism, thus lowering the bodies ability to burn fat effectively at rest whilst increasing glucose concentration in the blood.


Androstenedione is a direct precursor to testosterone that can be converted into estradiol dependent on the level of circulatory aromatase present in the system. Aromatase is predominantly released from lipid cells and increased in biological environments high in blood glucose. Dietary intake is often thought to be the only contributor to elevated blood sugar, however heighten glucocorticoid reaction also increases the concentration of glucose in the blood thus increasing the potential release of aromatase and subsequent aromatization of androgens.

Androstenedione is a direct metabolite of DHEA (dehydroepiandrosterone) which impacts neuro-protective qualities throughout control centers in the brain. Decrease of Androstenedione therefore not only impacts estrogen profile but also subsequently influences the reactions, neuro-protective androgens may have on the brain.

Poor release of LH (luteinizing hormone) is often noted in cases of exogenous hormone use. This, in turn, also has an impact on the availability of androstenedione, inevitably impacting testosterone levels and overall androgen health. Interestingly, LH plays a massive role in HDL metabolism, in that poor release and stimulation sets outcome of poor ongoing HDL production. Thus increasing probability of inflammatory mediated immune suppression occurs.

Considerations and conclusions

  1. Testosterone is regulated by the hypothalamus and pituitary gland.
  2. The hypothalamus secrets GnRH (gonadotropin regulating hormone) in generative pulses.
  3. In response to the release of GnRH, the pituitary releases LH (luteinizing hormone) and FSH (follicular stimulating hormone) which act on the testis.
  4. FSH acts on the Sertoli cells to produce sperm.
  5. LH stimulates the leydig cells to secrete testosterone.


Thus use of anabolic steroids needs to consider impact on leydig and Sertoli cells when use is prolonged or excessive. Essentially regulatory testing should be conducted as to determine when the system requires recovery from supra-physiological states as to avoid detrimental health consequences.

Before we can slate the use of exogenous hormone performance enhancement one needs to truly understand that there are immediate benefits too. The following positive changes are also associated with testosterone supplementation:

  1. Increased muscle mass
  2. Increased bone density
  3. Improved insulin sensitivity
  4. Improved hippocampus reaction
  5. Increased proprioception
  6. Improved stress response
  7. Reduced anxiety and depression
  8. Feeling absolutely indestructible

5 top Supplemental considerations one should consider when using exogenous hormones:

  1. Oxidation: Environments of supra-physiological concentrations of androgens often increase the rate of cholesterol metabolism, which in turn increases the proliferated release of cytokine reactions, namely IL- (interleukin-6) and TNF (tumor necrosis factor). Both IL-6 and TNF increase activity within initial innate and (possible) adaptive immune response (depending on the reaction and duration of inflammatory response). EFA (Essential fatty acids) coupled with Vitamin D and K2 (if needed) aid in modulating prostalgladin 2 reaction, which is mediated via the release (often premature in cases of steroid us) of AA (arachidonic acid), thus those whom supplement with EFA, Vit D and K2 are less likely to have exacerbated pro-inflammatory responses.
  2. Free radicals: Due to an increase of energy output (steroid make you stronger and improve endurance) there is a notable increase of free radical release. Molecular hydrogen is an effective element that is able to infiltrate every cell in the human body and thus reset pH variable within tissue. Essentially if your not only looking to limit the impact metabolites of energy production may have on your body, but also aim to improve overall recovery then the inclusion of molecular hydrogen may go a long way within your supplement strategy.
  3. Conjugation and modification aids: From sulphoraphane to DIM (3,3’ diindolylmethane) and many bioactive vitamins, the concentration of available precursors to both primary and secondary phase detoxification pathways goes a long way toward aiding hepatocytes (liver cells) in metabolizing excessive hormones.
  4. Phospholipids and fatty acid metabolism: the health of one’s hepatocytes determines the efficiency of detoxification, thus including elements such as choline, inositol and ALA (alpha linolenic acid) goes a long way toward ensuring hepatocytes do not become overloaded with fat, resulting in potential steatosis (fatty liver build up).
  5. Cortisol modulators: Phosphatidyl serine to Ashwaganda, both have very unique pathways in aid of the body’s need to modulate cortisol release. Management of cortisol release, essentially will enable a healthier ongoing immune reaction and overall bio-rhythm.

Moderation is key, knowing that everyone responds differently gives further cause for testing. Thus if you are using or considering the use of performance enhancement, test your physiological shifts! From transferase activity in the liver to cholesterol metabolism in the periphery, testing goes a long way in avoiding overuse and subsequent unwanted symptoms/disease.