Chapter 52: Androgens

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If you prescribe testosterone without understanding, you know, it's exact pharmacokinetics, you aren't just risking a few minor side effects.

You are, well, you're inviting irreversible physical mutations in your patients.

Yeah, and you're putting them at a severe risk for catastrophic thromboembolic events too.

I mean, it is one of those potent systemic chemical messengers we have.

Exactly.

When you introduce exogenous hormones into the human body, you are overriding this incredibly delicately balanced endocrine system.

And the collateral damage from doing that blindly is immense.

And that high stakes reality is exactly why we're tackling this today.

So welcome to your one -on -one tutoring masterclass from the Last Minute Lecture Team.

Glad to be here.

Our mission in this session is to conquer chapter 52 of Lane's Pharmacotherapeutics, which is all about androgens.

So for everyone out there prepping for clinicals or, you know, staring down a massive pharmacology board exam, we are going deep into the mechanisms, the absolute safety priorities and the clinical decision -making frameworks.

Right, and the central pharmacotherapeutic focus we really have to establish from page one is that the primary clinical application of androgens is managing androgen deficiency in males.

Okay, so that's the core therapeutic goal.

Exactly.

But because testosterone receptors exist in almost every organ system, you just can't isolate its effects.

You get the targeted benefit, but you also get a cascade of systemic physiological changes.

Which is a lot to manage.

So let's start with the baseline physiology to understand that cascade.

Like, where is this endogenous testosterone actually coming from when the body is functioning normally?

Well, in males, production is entirely localized to the lating cells within the testes.

We are looking at a daily endogenous production ranging from 2 .5 to 10 milligrams.

Okay, 2 .5 to 10.

Yeah, but those lating cells are essentially just the factory workers.

They don't decide when to work on their own.

They take their orders directly from the anterior pituitary gland.

Through signaling hormones.

Yes, via two specific ones, follicle stimulating hormone, or FSH, and luteinizing hormone, which is LH.

I always try to picture the feedback loop here because it's so important.

If plasma levels of testosterone start dropping, the pituitary senses that deficit, and it pumps out more FSH and LH to stimulate the testes.

Precisely.

Then as the testosterone levels rise back up in the blood, that rising concentration acts on the pituitary to suppress further release of those stimulating hormones.

It's essentially a biological thermostat.

Like that analogy.

Once the house hits the target temperature, the rising heat triggers the furnace to just shut off.

That negative feedback loop is really the governing dynamic of the entire endocrine system.

And as we'll see later, understanding that loop is the key to understanding why anabolic steroid abuse causes sterility.

Now, it's also crucial to realize this isn't exclusively a male hormone.

Yeah, I was actually shocked to learn how much of a role it plays in females.

Obviously, it's on a much smaller scale, but if males are pumping out up to 10 milligrams a day, what are the adrenal glands and ovaries actually producing in women?

It averages about 300 micrograms a day.

So it's 10 to 40 times less than male production.

Oh, wow, okay.

And it primarily comes from preandrogens secreted by the adrenal cortex and the ovaries, which are then converted into active testosterone out in the peripheral tissues.

Okay, so let's trace that active testosterone down to the cellular level.

When it finally reaches a target tissue, how does it actually alter the cell's behavior?

The mechanism of action is incredibly direct.

Testosterone is a steroid hormone, meaning it's lipid soluble.

So it just slides right in?

Exactly, it passes right through the cell membrane and binds to specific receptors that are just waiting in the cell cytoplasm.

Once they link up, this whole hormone receptor complex migrates entirely into the cell nucleus.

And what does it do there?

It binds directly to the DNA to promote the synthesis of specific messenger RNA molecules.

Those mRNA templates then produce the specific proteins that physically alter the tissue.

Wait, there's a clinical caveat here that I need to clarify from the text.

It points out that in certain specific tissues, like the prostate, the seminal vesicles,

and hair follicles,

the testosterone circulating in the blood isn't actually the active key.

Right.

The tissue has to actively transform at first.

Yes, that is a brilliant quirk of the pharmacology.

In those specific tissues, testosterone cannot unlock the receptor on its own.

It must first be metabolized locally into a byproduct called dihydrotestosterone, or DHT.

Oh, so it's the DHT doing the work.

Exactly.

Only the DHT can interact with the receptors to trigger mRNA synthesis in those specific areas.

That feels like a massive insight for clinical practice.

I mean, if a patient is experiencing aggressive male pattern baldness or prostate enlargement, it's not just about the raw testosterone, it's about what's in their blood, is it?

No, it's about how actively those specific tissues are converting it into DHT.

Which perfectly sets up the physiologic effects we need to monitor.

When that mRNA synthesis ramps up, the physical transformations are profound, right?

Oh, absolutely.

In males, the searching production triggers puberty.

You see rapid growth of bone and skeletal muscle

and enlargement of the larynx, which is what deepens the voice.

But there's a crucial pharmacokinetic detail for anyone treating pediatric patients here.

Testosterone also accelerates epiphyseal closure.

Yes, meaning it tells the bone growth plates to fuse.

So while it causes an initial growth spurt, it also initiates the countdown to when bone growth ceases entirely.

Exactly.

Now following puberty, endogenous androgens become an absolute requirement for stremitogenesis.

You just cannot produce or mature a sperm without them.

And what about in females?

In females, that physiologic baseline of 300 micrograms primarily works to promote clitoral growth and maintain normal libido.

We also have to highlight the systemic anabolic and erythropoietic effects because these directly dictate our therapeutic goals.

Right, the muscle and blood effects.

Yeah, testosterone promotes the growth of skeletal muscle by forcing those fibers to synthesize more protein.

But interestingly, giving exogenous testosterone to a healthy adult male has a relatively modest effect on muscle growth.

Because his endogenous production is already nearly saturating the available receptors.

Right, but if you give it to a youth or a female patient, the anabolic muscle growth is dramatic.

Very dramatic.

And the erythropoietic effect is just as critical.

Testosterone directly promotes the synthesis of erythropoietin or EPO in the kidneys.

And that EPO acts on the bone marrow to drastically increase red blood cell production.

The numbers on this are actually staggering.

If you administer testosterone to a female patient, her hematocrit rises and her hemoglobin increases by an average of 4 .3 grams per deciliter.

Wow, 4 .3.

Yeah, but in men, because their baseline EPO drive is already elevated by their natural testosterone, giving them exogenous androgens only bumps their hemoglobin by about one gram per deciliter.

That differential is massive.

And I guess it explains exactly why men naturally run higher hematocrites than women.

It does.

Now taking all of these physiological effects, the secondary sex characteristics, the muscle synthesis, the erythropasis, we really have to look at the rational therapeutic goals.

When do we actually prescribe this?

Well, the 2018 FDA guidelines and the Endocrine Society protocols are incredibly strict on this.

Testosterone is exclusively approved for patients with confirmed testosterone deficiency due to hypogonadism.

Right, we're talking about documented pathology here.

Like a hereditary defect or pituitary failure or primary dysfunction of the testes.

In those specific cases of hypogonadism, therapy successfully restores libido, ejaculate volume, and supports the development of secondary sex characteristics.

Though it is vital to note that exogenous therapy does not restore fertility.

That's a huge point.

Let me pose a very common clinical scenario though.

Say a 75 -year -old male patient comes into the clinic.

He feels chronically fatigued, his libido is down, and his lab work shows his testosterone levels are like less than half of what they were when he was 20.

Does he get a prescription?

He does not.

The FDA explicitly clarified that lowered testosterone due strictly to normal aging does not meet the criteria for hypogonadism.

So we aren't treating the natural aging process.

We are treating documented hormonal pathology.

Exactly, the distinction clinicians must make.

Now you will see a few highly specific off -label uses.

Short courses are sometimes utilized for delayed puberty in males if the psychological distress is severe.

Okay, that makes sense.

It is also a cornerstone in gender -affirming therapy for transgender men.

And occasionally, it's prescribed off -label for menopausal women experiencing severe fatigue or reduced libido.

But that requires microscopic doses, right?

Yes, mimicking that 300 -microgram premenopausal baseline and it's usually paired with estrogen.

Historically, wasn't it also used for refractory anemias because of that massive EPO stimulation we talked about?

It was, yeah.

But modern pharmacology gave us safer, much more targeted EPO -stimulating agents.

So testosterone has really fallen out of favor for anemia.

Which is fortunate because leaning on testosterone for its benefits means accepting a really heavy burden of adverse effects.

Every physiological benefit we just discussed becomes a danger if the dosing or patient selection is wrong.

Very true.

Let's talk about those safety priorities across the lifespan.

The most common and visible adverse effect is virilization in women, girls, and pre -pubertal boys.

What does that look like clinically?

If a female patient is exposed to high doses, you see severe acne, deepening of the voice,

proliferation of facial and body hair, male pattern baldness, and clitoral enlargement.

The absolute clinical priority here is that the medication must be halted at the very first sign of these changes.

I mean, if you wait,

structural changes to the vocal cords and the hair follicles become permanent.

You cannot undo a deepened voice or clitoral enlargement once the tissue has remodeled.

You really can't.

And for pediatric patients, the hidden danger goes right back to the growth plates.

It will accelerate epiphyseal closure and permanently stunt their adult height.

So how do you monitor for that?

To prevent it, any child on androgen therapy requires a radiographic examination of the hand and wrist every six months that lets you monitor their bone age versus their chronological age.

Okay, so moving across the lifespan, pregnancy is an absolute contraindication, right?

Absolutely.

The teratogenic risks vastly outweigh any possible benefit.

Exposure causes severe fetal masculinization.

Like what?

Resulting in vaginal malformations and even the formation of a pseudoscrotum in female fetuses.

And breastfeeding is also contraindicated because the hormone readily passes into breast milk.

And then we hit the older adult population.

We just established that testosterone spikes red blood cell production.

That erythropoietic effect is great if you're trying to build blood volume, but in a 65 -year -old man, it's a ticking time bomb for a stroke.

Exactly.

Which brings us to the severe cardiovascular risks and why testosterone is on the Beers criteria.

Yeah, the Beers criteria explicitly identifies it as potentially inappropriate for older adults.

The 2018 FDA safety alert highlighted the severe risk of thromboembolic events.

So myocardial infarctions, strokes, deep vein thrombosis, and pulmonary embolisms.

Because when you spike red blood cell production, you increase the hematocrit.

You're essentially thickening the blood, making it vastly more prone to clotting in an already aging vascular system.

It also causes the retention of salt and water, right?

Yeah, and that resulting edema is highly dangerous for any patient with existing heart failure.

Plus, it actively degrades the patient's lipid profile.

By lowering their good HDL cholesterol and elevating their bad LDL cholesterol.

Which just accelerates atherosclerosis.

Finally, we must mention the prostate.

While current evidence doesn't show that androgens spontaneously cause prostate cancer, they act as a potent fuel for the growth of existing prostate cancer cells.

Active prostate cancer is a strict contraindication.

So the therapeutic window is incredibly tight.

How do we actually deliver this drug safely?

Let's break down the clinical decision making around the different preparations.

Because table 52 .1 in the text, gives us a lot of options with very different pharmacokinetic profiles.

Yeah, and selecting the right preparation dictates the patient's entire experience.

Let's look at oral testosterone,

undecanate brand names, like Jitenzo, Kaizotrex, and Tolando.

What's the catch with the oral ones?

The pharmacokinetic catch here is they must be administered with food to achieve absorption.

But generally, oral formulations are not first line agents because the androgenic blood levels they produce are just too erratic.

Then you move to the intramuscular esters like testosterone, sippianate, and ananthate.

These are long acting depo injections, usually given every two to four weeks.

But the pharmacology of the ester chain creates a major clinical flaw.

Right.

The esker dictates how fast the hormone releases from the muscle into the blood.

So right after the injection, you get a massive bolus dump.

Blood levels shoot way above the therapeutic maximum.

Then over the next few weeks, it slowly decays, crashing below the therapeutic minimum just before the next shot.

Right, and that pharmacokinetic roller coaster translates into a literal, emotional, and physical roller coaster for the patient.

They experience wild corresponding fluctuations in their libido, energy levels, and mood.

To bypass that roller coaster, clinicians can use testosterone implants like Testapol.

These are subdermal pellets that provide wonderfully steady, continuous blood levels.

But the trade -off is they require an invasive surgical procedure every three to six months to implant new pellets under the skin.

Which leads many patients to opt for transdermal options, but this is where clinicians must address a severe black box warning.

This is critical.

We are talking about testosterone gels like Endrogel, Testim, Fortesta, and Bogelxo, as well as the topical solution Axaron.

The black box warning states that secondary exposure to these topicals on unwashed clothing or bare skin has resulted in the severe virilization of children and female partners.

It's essentially secondhand smoke, but for hormones.

Just being in close physical proximity to the user can be dangerous.

Why does this happen so easily?

It comes down to the absorption mechanics of the gel.

Only about 10 % of the applied dose is actually absorbed into the patient's skin.

The remaining 90 % stay sitting right there on the surface of the skin after the gel dries.

90%, that's wild.

The text highlights a terrifying study where the blood levels of testosterone in female partners completely doubled after just 15 minutes of intimate skin -to -skin contact with a gel user.

Just 15 minutes.

And for children whose baseline testosterone is near zero, that microscopic transfer causes aggressive behavior, advanced bone age, and premature sexual development.

Preventing that transfer requires rigid patient education.

Gel users must wash their hands with soap and warm water immediately after application.

And once the gel dries, they must cover the application site with clothing.

Right, they are required to wash the site thoroughly with soap prior to any anticipated skin -to -skin contact with another person.

And because the hormone can wash off before it fully absorbs, they must wait five to six hours after applying before they shower or swim.

Wow, for the topical solution, Exeron,

the application is unique.

It has an alcohol base and is formulated specifically for the armpit.

Yeah, you pump it onto a dedicated applicator and apply it to the axilla.

But because of that alcohol base, it is highly flammable until it fully dries, meaning patients absolutely cannot smoke or be near open flames during application.

There is also a nasal gel formulation called Natesto that avoids the transdermal transfer risk.

It is administered via a metered dose pump directly into the nasal cavity.

But it trades the transfer risk for localized adverse effects, right?

Like rhinorrhea, severe runny nose and epistaxis or nosebleeds.

Yes.

And the administration algorithm for Natesto is wonderfully specific and it's a great example of how underlying anatomy dictates drug delivery.

You don't just shove it up the nose.

Right, the patient has to blow their nose first to clear the mucosa.

You insert the pump, but you have to aim the tip outward toward the lateral nostril wall, completely avoiding the septum.

The reasoning there is vital.

The septum is fragile cartilage.

Chronic application of a potent medication there can easily cause septal necrosis or perforation.

Yikes.

Yeah.

The lateral wall provides a much safer, robust mucosal surface for systemic absorption.

After depressing the pump, you wipe the tip against that lateral wall to transfer all the gel, lightly massage the nose and the patient must avoid blowing their nose or sniffing aggressively for at least one hour.

Understanding those delivery mechanics is so satisfying because it directly connects the pharmacology to the patient's daily routine.

Now we have to tackle the inevitable question every clinician gets regarding the abuse syndrome, sports doping and misuse.

Let's look at the actual data.

Yeah.

Do massive doses of anabolic steroids physically work for athletic performance?

The clinical reality is yes, they do.

And to be clear on terminology, the text emphasizes that androgens and anabolic steroids are clinically the exact same thing.

Yes.

The cellular receptors mediating the androgenic masculinizing actions are the exact same receptors mediating the anabolic muscle building actions.

You cannot separate them.

So what about their efficacy?

The text cites a controlled study where subjects taking testosterone who engaged in strength training gained a 13 pound increase in muscle mass in just 10 weeks.

The control group who did the exact same exercise without the drug only gained four pounds.

Wait, 13 pounds compared to four?

That is a massive physiological difference.

It's physically forcing the muscle fibers to hypersynthesize protein because the massive doses have completely saturated every available androgen receptor in the body.

It is easy to see why the appeal exists for athletes, but the physiological cost is devastating.

If we go back to our thermostat analogy from the beginning, injecting massive exogenous doses of androgens is like cranking the heat in the house to 1 ,000 degrees.

The pituitary senses that massive heat wave and completely shuts off the release of LH and FSH.

Exactly.

Without LH and FSH stimulating the testes, the endogenous factory shuts down entirely.

This results in testicular atrophy, sterility, and ironically, chynicomastia, the development of breast tissue.

Furthermore, athletes often acquire what are known as 17 alpha -alkylated compounds.

We largely abandon these in standard clinical practice because of their toxicity.

Very toxic.

To make an oral steroid survive the brutal first pass metabolism in the liver,

chemists altered the molecule at the 17 alpha -cardin position.

But that structural armor makes it incredibly difficult for the liver to process, putting the organ under immense strain.

Right, it leads to severe hepatotoxicity, including cholestatic hepatitis, jaundice, and hepatocelular carcinoma.

It also wreaks havoc on the kidneys.

And beyond the organ damage, it creates a profound abuse and withdrawal syndrome.

Long -term users become psychologically preoccupied with the drug.

When they stop, they experience a severe abstinence syndrome characterized by depression, fatigue, and craving that is remarkably similar to the withdrawal scene with alcohol, opioids, or cocaine.

Because of this well -documented abuse potential,

all androgens are heavily regulated as Schedule III controlled substances.

We have covered an immense amount of complex pharmacology today.

Let's bring all of these concepts together into a clinical summary framework.

Sounds good.

If you have a patient with confirmed hypogonadism, how do you safely monitor them from day one?

Before you ever write the prescription,

you must collect comprehensive baseline data.

You need a serum testosterone concentration to confirm the deficit.

You need a complete blood count, specifically looking at the hematocrit to establish their baseline clotting risk.

What else?

You need a full lipid panel, liver function tests, and a prostate -specific antigen, or PSA, test to screen for existing prostate cancer.

Okay, so once therapy begins, that hematocrit is your canary in the pulmine.

It must be checked at the three -month mark and then annually after that to ensure the erythropoietic effect isn't thickening the blood to a dangerous degree.

Yes, everything else, the serum testosterone, lipids, liver function, and PSA is checked after one year.

And there is a hard, non -negotiable rule for the PSA monitoring.

If it is greater than 4 .0 nanograms per milliliter or if it jumps more than 1 .4 nanograms per milliliter above their established baseline, you must immediately refer that patient to a urologist to evaluate for prostate cancer.

And for patient education, your core priorities are ensuring they monitor themselves for edema and weight gain caused by water retention.

You must instruct female patients to halt the medication at the absolute first sign of virilization to prevent irreversible vocal cord or clitoral changes.

You must also confirm that any female patient of childbearing age is using completely reliable contraception due to the severe tardogenicity.

And of course, you must preach religious hand washing and clothing coverage for anyone using a transdermal gel to prevent that secondhand hormone transfer.

That brings us to the end of chapter 52.

On behalf of the last minute lecture team, thank you for joining us for this deep dive.

We deeply appreciate your dedication to mastering clinical pharmacology.

You are putting in the rigorous work to understand not just what these drugs do, but exactly how they do it.

And that is what keeps your future patients safe.

Keep reviewing those intracellular mechanisms and those strict monitoring parameters.

The details matter in endocrinology.

But before you close your books and step away for the day, I wanna leave you with one final thought to mull over.

We learned today that endogenous testosterone naturally drops by half by the time a male reaches age 80.

But we also learned the FDA strictly forbids treating that age -related decline, reserving therapy exclusively for documented pathological hypogonadism.

Given how profoundly this hormone impacts energy, muscle mass and mood, wait, sorry.

Given how profoundly this hormone impacts energy, muscle mass and mood is our rigid medical boundary between pathological hypogonadism and normal aging, missing a critical nuance about the quality of life in the modern lifespan.

Keep that in the back of your mind as you head into clinicals.

Good luck studying and we'll catch you on the next deep dive.