Chapter 25: Estrogens and Androgens

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You know, when you think about the master regulators of human reproduction, you might picture this incredibly complex, highly specialized biological machinery,

but at the very base of it all, the starting material for both estrogen and testosterone is just cholesterol, like a humble blob of fat, and it's the raw material for everything from embryonic development and puberty to modern contraception and even targeted cancer treatments.

It's honestly a remarkable biological transformation.

The body takes that basic cholesterol precursor and through this series of really specific enzymatic steps, you know, clipping a carbon chain here, maybe adding a hydroxyl group there, it synthesizes these incredibly powerful sex hormones.

And we are talking about molecules that can alter the physical structure of bone, right?

Like they change blood clotting factors, they dictate cellular growth across the entire body.

Oh, absolutely.

They're systemic powerhouses.

And deciphering how we manipulate those molecules is our mission for you today.

We are doing a custom deep dive into the pharmacology of estrogens and androgens.

This is specifically tailored for those of you tackling this material for the first time.

Right.

So if you're a college student staring down a massive pharmacology exam right now, grab a coffee.

We're taking all this dense drug information and translating it into a logical clinical roadmap.

Yeah, exactly.

And we're going strictly by the book today, specifically Chapter 25 of Lippincott Illustrated Reviews, Pharmacology, the seventh edition.

Right.

And if you look at the opening roadmap in the chapter, Figure 25 .1, it lays out our whole plan.

We have to start at the biological baseline.

I mean, before we can understand how a synthetic contraceptive works or, you know, why a specific prostate cancer drug is chosen, we need to understand the endogenous estrogens.

The ones the body makes naturally.

Exactly.

And from there, we can explore serums, how we combine hormones for birth control, and finally flip to the male hormonal axis, which mirrors those exact same principles.

OK, let's unpack this.

How do we get from a basic cholesterol molecule to the powerful hormones that shape human reproduction?

Well, let's start with that natural baseline.

When we talk about endogenous estrogens, we're really talking about a trio of hormones.

People often call them the big three.

Right.

Estradiol, Estrone, and Estriol.

Got it.

And I know Estradiol is like the heavy hitter, but how do these three actually divide the labor in the body?

So Estriol is definitely the most potent of the three.

It's produced and secreted mostly by the ovaries, so that makes it the principal estrogen circulating in premenopausal women.

But Estrone is a bit different.

It only has about one third the potency of Estriol.

Oh, wow.

So why is it important?

Well, what makes Estrone clinically significant is that it becomes the primary circulating estrogen after menopause.

Ah, because the ovaries are powered down.

Exactly.

At that point, Estrone is generated mainly in pericoral fat tissue from a precursor molecule called DHEA, and then finally you have Estriol.

Which is the weakest one, right?

It is the weakest, yeah.

Yeah.

But it appears in these massive quantities during pregnancy because it's actually synthesized directly by the placenta.

Okay.

So the body just swaps the primary hormone based on the life stage.

Estradiol for premenopause, Estrone for postmenopause, and Estriol for pregnancy.

Precisely.

But what happens when these molecules actually reach a target cell?

Because a lot of drugs we look at, they just bind to a receptor on the outside of a cell membrane, they ring the doorbell, and some secondary messenger does all the work inside.

Right, but steroid hormones operate on a completely different level.

This goes back to figure 25 .2 in the text showing the mechanism of action.

Because they are derived from cholesterol, they're highly lipophilic.

Meaning they're fat soluble.

Right.

So they don't need to ring the doorbell at all.

They just diffuse directly through the lipid bilayer of the cell membrane and float right into the interior.

Wow.

Yeah.

And once they're inside, they bind with really high affinity to specific nuclear receptor proteins.

So these hormones don't just knock on the cell's door.

They have a VIP pass straight into the nucleus to rewrite the instruction manual.

That is exactly the mechanism.

Yeah.

The steroid receptor complex binds directly to regulatory DNA sequences on the chromatin.

By doing that, they literally trigger or suppress RNA synthesis.

So they are actively dictating the synthesis of specific proteins.

Exactly.

And this is why their effects take a little time to manifest, you know.

But they're so widespread and profound across different organ systems.

Which brings us to the clinical application of this baseline, right?

Postmenopausal hormone therapy.

Right.

Because when the ovaries start producing ester ale, women can experience some pretty severe motor symptoms, like those really intense hot flashes.

Oh, absolutely.

And urogenital atrophy plus a really rapid loss of bone density.

And supplying exogenous estrogen can actually alleviate those symptoms, right?

It's like figure 25 .3 spells out these benefits perfectly.

It reestablishes that negative feedback loop to the hypothalamus to cool down the hot flashes.

Yeah.

It restores the local tissue health in the urogenital tract.

And crucially, it blocks the resorption of bone, which protects the skeleton from osteoporosis.

But there is a major clinical caveat with that approach today, right?

There is a huge caveat.

While systemic estrogen therapy absolutely decreases the frequency of osteoporotic fractures, current clinical guidelines strongly prefer non -hormonal drugs for long -term bone health.

Bisphosphonates, specifically.

Exactly.

The whole landscape of hormone therapy has shifted dramatically because of the risks associated with systemic estrogen exposure.

The modern standard is to prescribe hormone therapy at the lowest effective dose for the shortest possible duration.

Just to get them through the worst of the symptoms.

Right.

And furthermore, if a patient is only experiencing, say, urogenital atrophy,

a clinician will just treat that locally with a vaginal cream or a ring that keeps the hormone out of the systemic circulation entirely.

Because once you put estrogen into the systemic circulation, you have to worry about the uterus.

You do.

And this brings up one of the most critical non -negotiable rules in reproductive pharmacology.

Like, you have to know this.

If a woman has an intact uterus, estrogen must always be prescribed alongside a progestogen.

Yes.

If you give unopposed estrogen to a patient with a uterus, that hormone will just do what it's designed to do.

It will stimulate the aggressive growth of the endometrial lining.

And over time.

Over time, that unchecked proliferation significantly increases the risk of endometrial carcinoma.

It's a huge cancer risk.

But by adding a progestogen, you stabilize that lining and mitigate the risk.

Okay.

But what if the patient has had a hysterectomy?

Well, if the uterus is physically absent, that specific cancer risk is gone.

So in that case, systemic estrogen can actually be given alone.

Makes sense.

Let's talk about the actual pills used in these therapies, though.

Because if natural estradiol is the most potent, it just seems logical that we would put that in a pill.

But oral contraceptives use synthetic versions like ethanol escradile.

Why do we need the modification?

It is all about surviving the liver.

If a patient swallows a pill of natural, unmodified estradiol, it gets absorbed from the gut and goes straight to the liver via the portal vein.

And the liver just tears it apart.

Oh, aggressively.

The liver enzymes metabolize and inactivate the vast majority of it before it ever reaches the general circulation.

Right.

The first pass metabolism.

Exactly.

It renders oral natural estradiol highly ineffective.

So the liver acts like a security checkpoint and the natural estradiol gets confiscated immediately.

Yep.

So the synthetic versions are essentially wearing a chemical disguise to slip past.

That's a great way to put it.

By adding a specific chemical group, an ethanol group, pharmacologists created ethanol estradiol.

And this synthetic molecule resists that first pass hepatic metabolism.

Oh.

Yeah.

It's highly fast soluble.

It gets stored in adipose tissue, it releases slowly, and it boasts a much higher potency and prolonged action compared to the endogenous hormone.

But slipping past the liver with a highly potent synthetic estrogen carries a cost, doesn't it?

I mean, looking at the adverse effects visual in figure 25 .4, it's serious.

It is very serious.

Beyond the common stuff like nausea, fluid retention, or breast tenderness, you have Severe cardiovascular warnings, hypertension, myocardial infarction,

and crucially, thromboembolism.

Right.

Synthetic, systemic estrogen basically makes the blood more prone to clotting and that thromboembolic risk is a primary factor in patient selection.

It's why clinicians have to monitor these prescriptions so closely.

Which sets up this really fascinating pharmacological problem.

We have this hormone that provides incredible benefits like building strong bones, but it risk of blood clots and uterine cancer.

Exactly.

So is there a way to get the good effects without the bad?

Well, that dilemma is exactly what led scientists to develop a class of drugs called selective estrogen receptor modulators, or CIRMS.

The whole goal here was to engineer a molecule that acts as an estrogen agonist in the tissues where we want it, but an antagonist in the tissues where we don't.

Oh, like smart bombs.

Exactly like smart bombs.

You could think of a CIRM as a master key that turns the lock perfectly in some doors, but intentionally jams the lock in others.

That's incredible.

How is that even possible?

Well, this tissue selectivity works because estrogen receptors in different parts of the body actually have slightly different configurations, and they rely on different local co -activators.

Okay, let's look at meloxapine as an example.

This one is prescribed for postmenopausal osteoporosis,

and the chapter references figure 25 .5, which is this graph proving that in bone tissue, meloxapine acts as an agonist.

It mimics estrogen, decreases bone resorption, and over a 24 -month period, the data shows it steadily increases hip bone density compared to a placebo.

Yeah, it's highly effective for bone.

But what makes it so valuable is what it does everywhere else.

In the breast and the uterus, meloxapine acts as a strict antagonist.

It blocks the receptor.

Right.

So it provides the bone -building benefits of estrogen without stimulating the endometrium.

That effectively eliminates the risk of endometrial cancer that comes with traditional estrogen therapy.

That is so elegant.

Then we have tamoxifen, which is probably the most famous serum.

It's primarily used to treat estrogen receptor -positive metastatic breast cancer.

Yes.

It competes with estrogen, binding to the receptors in the breast tissue, and basically shutting down the hormonal fuel the tumor needs to grow.

But wait, isn't there a catch with tamoxifen?

There is a very dangerous catch.

While tamoxifen is an antagonist in the breast, it actually acts as an agonist in the endometrium.

Oh no.

Unlike reloxapine, tamoxifen stimulates the uterine lining.

This can cause endometrial hyperplasia and potentially malignancies.

Wow.

So they have to really watch that.

Exactly.

That risk forces clinicians to strictly limit the duration of tamoxifen therapy.

There's also a major drug interaction warning with tamoxifen, right, involving the liver cytochrome P450 system, because tamoxifen is technically a pro -drug.

It is a pro -drug, yes.

It needs the liver to activate it.

Specifically, it relies heavily on the CYP2D6 isoenzyme in the liver to be converted into its active cancer -fighting metabolites.

Okay, so what happens if someone is a poor metabolizer?

Well, if a patient has a genetic polymorphism that makes them a poor metabolizer, or, and this is common, if they are taking a drug that inhibits CYP2D6, like certain SSRI antidepressants… They fail to activate the tamoxifen?

Exactly.

The drug simply won't work, leaving their breast cancer undertreated.

That is terrifying, and it just shows why understanding metabolism pathways is just as critical as knowing the drug's primary mechanism.

Okay, one more CIRM.

Clomaphene.

This one is used for infertility, and it works by manipulating the brain, not the reproductive organs directly.

Right.

Clomaphene interferes with the negative feedback loop.

Normally, circulating estrogens tell the hypothalamus, hey, we have enough hormone, you can stop stimulating the system.

Like a thermostat.

Right.

But clomaphene blocks those receptors in the hypothalamus.

It essentially blinds it to the estrogen and the blood.

So believing estrogen levels are dangerously low, the hypothalamus releases a massive surge of gonadotropin -releasing hormone.

Which travels down to the pituitary gland, triggering a release of gonadotropins like LH and FSH, which then just slam the accelerator on the ovaries to stimulate ovulation.

Precisely.

And because you are chemically supercharging that system, the most famous side effect is an increased risk of multiple gestations.

Yeah.

Usually twins.

Wow.

Because you are totally overriding the body's natural pace setting.

You are.

Now, everything we've discussed so far revolves around estrogen, right?

The hormone that builds the reproductive environment.

Right.

But to understand full cycle regulation and contraception,

we have to look at the hormone that stabilizes and maintains that environment,

progesterone.

Okay.

Let's look at the physiology here.

If we visualize the natural rhythm of a typical 28 -day menstrual cycle, and the expert literally walks us through the graph in figure 25 .6 here.

The first half is relatively quiet on the progesterone front.

Very quiet.

But right around day 14, you get a sharp, dramatic spike in luteinizing hormone, or LH, alongside a smaller bump in FSH.

And that surge triggers ovulation.

Right.

And estrogen levels are kind of waving up and down through all this.

Yeah.

But progesterone does something entirely different.

Yeah.

It stays flat for the first two weeks, and then immediately after ovulation, it builds into this massive dominant plateau for the entire second half of the cycle, the luteal phase.

Exactly.

And that sustained high level of progesterone is doing two vital things.

First, it is transforming the uterine lining into a lush, secretory endometrium, perfectly preparing it for a fertilized embryo to implant.

And the second thing.

Second, it sends a strong negative feedback signal to the brain, suppressing any further release of gonadotropins so no new follicles develop.

But if conception does not occur, the corpus luteum in the ovary degrades and stops producing progesterone.

So that massive plateau just drops off a cliff.

And that sudden, abrupt withdrawal of progesterone support is the chemical trigger that causes the uterine lining to shed, initiating menstruation.

That's the cycle.

Here's where it gets really interesting.

We use synthetic progestins to prevent pregnancy by tricking the body into thinking it's already in that luteal phase.

It's brilliant.

By understanding that natural rhythm, pharmacologists realize they could create highly effective contraceptives.

If you give a patient synthetic progestins every day, you artificially maintain that negative feedback loop.

So the pituitary never releases that mid -cycle LH surge.

Exactly.

And if there's no LH surge, ovulation never happens.

And we use synthetic progestins like levonorgestrel or nortendrone because, just like natural estrogen, natural progesterone is destroyed by first -pass metabolism in the liver.

Yep, same liver problem.

But the chemical structure of these synthetics brings its own set of problems.

If you look at figure 25 .7, a lot of them are derived from 19 -nortestosterone, meaning they look molecularly similar to male hormones.

Right.

And because of that structural lineage, these specific progestins possess unintended androgenic activity.

Male -like activity.

Exactly.

They can bind to testosterone receptors, causing male pattern side effects like acne, weight gain, or hirsutism, which is excess facial hair.

So if the clinician has a patient experiencing severe acne on levonorgestrel, they need a pharmacological pivot.

They do.

They might switch the patient to a different progestin, like drospironone.

Oh, OK.

Drospironone is specifically engineered to lack that androgenic activity, so it's great for clearing up acne.

But, and this is key, you can't just hand it out without monitoring, because drospironone acts as an anti -mineralic corticoid.

OK, let's break that down.

Mineralic corticoids, like aldosterone in your kidneys,

normally help your body excrete potassium.

Right.

So if you give a drug like drospironone that blocks that action,

the body retains potassium.

Oh, I see where this is going.

Yeah.

If that patient happens to be on other medications that also increase potassium, like an ACE inhibitor for high blood pressure,

you are suddenly risking severe hyperkalemia.

Which can cause fatal cardiac arrhythmias.

Exactly.

It's a perfect example of why you have to understand the specific chemical lineage of a drug, not just its broad category.

Truly.

OK, let's touch quickly on the opposite action, antiprogestins.

The main one mentioned is mefapristone.

Also known as Ru486.

So if progesterone is required to maintain the lush uterine lining for a pregnancy,

mefapristone acts as a direct competitive receptor antagonist.

It binds to the progesterone receptors and just blocks the hormone from doing its job.

Right.

And without that hormonal support, the uterine lining breaks down, resulting in the termination of the pregnancy.

OK, so we've explored estrogen and progestin separately.

Let's put them together.

How do combination contraceptives use these two hormones in tandem as a dual threat mechanism to prevent pregnancy?

It's a really effective team -up.

The exogenously administered estrogen primarily blunts the release of FSH from the pituitary, which halts the development of a new ovarian follicle.

OK.

Simultaneously, the progestin blunts the LH secretion, which prevents the mature follicle from ovulating.

And there's a secondary defense, too.

Yes.

The progestin also thickens the cervical mucus, creating this dense physical barrier that severely hampers the ability of sperm to enter the uterus.

It's totally comprehensive.

Now, the oral pill is obviously the most common delivery method, but figures 25 .8 and 25 .9 walk us through some alternative formulations, and they each come with very specific clinical

like the transdermal patch.

You apply it weekly for three weeks, then take a week off.

And it bypasses the liver initially, but the total exposure is different.

Significantly different.

The patch delivers a much higher total exposure to estrogen over time compared to a standard oral pill.

And because we know estrogen exposure correlates with cardiovascular risks, this is a crucial factor.

It's also less effective based on weight, isn't it?

Yes.

Pharmacokinetic data shows the patch is notably less effective at preventing pregnancy in patients weighing more than 90 kilograms.

Good to know.

What about the injectable progestin?

Madroxyprogesterone acetate, commonly known as DepoProvera.

It provides three months of coverage with a single intramuscular shot, which sounds incredibly convenient.

It is convenient, but it carries a massive warning regarding bone health.

Madroxyprogesterone acetate suppresses estradiol levels in the body to the point where it can contribute to significant bone loss, predisposing the patient to osteoporosis.

Wow.

So how long can someone stay on it?

The strict clinical rule in the text is that this injection should not be used continuously for more than two years unless, of course, the patient has absolutely no other contraceptive options.

That's a major limitation.

And clinicians also have to counsel patients that after stopping the injections, the return to baseline fertility can be delayed for several months.

Plus, significant weight gain is a highly common side effect.

Okay.

Then you have the subdermal implant, etonogestrel, which is a tiny rod placed under the skin of the arm that lasts up to three years.

But similar to the patch, efficacy can be compromised by patient weight.

It may be less effective in women who weigh more than 130 % of their ideal body weight.

This is why patient -specific tailoring is so important.

And speaking of which, when we talk about systemic contraceptives, we absolutely must highlight the contraindications, like who should never be prescribed a standard estrogen containing combination pill.

The most critical bold print contraindication in the text is women over the age of 35 who smoke.

It's a huge red flag because the combination of systemic synthetic estrogen and the vascular damage caused by smoking in an older patient creates just an unacceptable risk for severe cardiovascular events.

We're talking thromboembolism, myocardial infarction, and stroke.

So for that specific population, a progestin -only method is strictly required.

Exactly.

There's also a drug interaction that patients frequently ask about, which is, do antibiotics make birth control fail?

Oh, right.

People always wonder if that's just an urban legend.

It's not an urban legend.

There is a distinct pharmacological mechanism here.

Estrogen undergoes a process called enterohepatic recycling.

Right.

The liver secretes estrogen into the bile, which dumps it into the intestines, and then the normal healthy bacteria in your gut actually hydrolyze that estrogen.

They basically unpack it.

Yeah, they unpack it so it can be reabsorbed through the intestinal wall and put back into the bloodstream.

Exactly.

So if a patient takes a broad -spectrum antibiotic,

it eradicates those helpful gut bacteria.

The recycling plant shuts down.

The estrogen is never unpacked and reabsorbed.

It's just excreted.

Right.

And this causes the circulating serum levels of estrogen to plummet, which can lead to contraceptive failure and an unintended pregnancy.

Fascinating.

Okay.

Let's shift our focus to the male hormonal axis, androgens and antiandrogens.

The really cool part is that we apply the exact same physiological logic and feedback principles we just learned to a completely different set of organs.

The feedback loop is a mirror image.

If you look at figure 25 .11, the hypothalamus releases GnRH, which signals the anterior pituitary to release LH and FSH.

Those hormones travel down to the testes.

There, LH stimulates the lating cells to manufacture and secrete testosterone.

As that testosterone accumulates in the blood, it loops all the way back up to the pituitary and hypothalamus, binding to receptors to shut off the release of GnRH and LH.

It's that classic negative feedback loop again, regulating the system precisely like a thermostat regulating the temperature in a room.

Exactly.

But the way testosterone interacts with different tissues is highly specialized.

In muscle tissue and the liver, testosterone itself is the active molecule that binds to the receptor.

Okay, but what about other areas?

Well, if the hormone wants to exert an effect in the prostate gland, the seminal vesicles, or the skin, it requires a chemical upgrade.

A chemical upgrade.

Yeah, in those specific target tissues, testosterone must be converted by a local enzyme called 5 -alpha -reductase.

5 -alpha -reductase, got it.

This enzyme transforms testosterone into 5 -alpha -dihydrotestosterone, or DHT.

In the prostate and the skin, DHT is the active ligand that actually binds to the receptor to drive cellular growth or cause things like male pattern baldness.

Okay, so if a patient requires testosterone replacement therapy for a medical condition, how do we deliver it?

Because we already established that oral natural estrogen gets destroyed by the liver.

Is the same true for oral natural testosterone?

It is.

First pass metabolism completely inactivates oral natural testosterone.

So what are the options?

Well, figure 25 .2 post shows two distinct graphs.

If you administer it via a deep intramuscular injection, using an esterified version like testosterone and anthate, the patient experiences a severe pharmacokinetic roller coaster.

Oh, I see.

Their serum testosterone levels just spike massively on day one, rocketing far above the normal physiological range, and then slowly decay over the next two weeks.

Right, and that roller coaster causes massive mood and energy swings.

This is why transdermal patches or daily topical gels are generally preferred.

Because a patch delivers a constant measured dose through the skin directly into the bloodstream.

It keeps the patient's serum levels in a steady natural band over 24 hours.

Exactly.

Now, pharmaceutical companies did eventually figure out how to make an oral testosterone pill by chemically modifying it, specifically through 17 -alpha -alkylation, drugs like methyl testosterone.

But didn't that cause issues?

Yes.

That structural alteration makes the drug notoriously toxic to the liver.

Oral -alkylated androgens carry a high risk of serious hepatic adverse effects, so they are rarely the first choice.

Good to know.

We also need to address the cultural myths surrounding these hormones.

You see anti -aging clinics everywhere advertising testosterone and DHEA as the fountain of youth for older men.

So what does this all mean for those fountain of youth claims?

The clinical data in the text is definitive on this.

Therapeutic testosterone replacement is strictly indicated for treating medical hypogonadism.

Like primary testicular failure or secondary pituitary dysfunction.

Right.

Or for treating severe chronic wasting diseases associated with HIV or advanced cancer.

It is explicitly not approved or recommended for treating the natural decline in testosterone associated with normal aging.

No fountain of youth.

No.

Furthermore, clinical trials show no definitive evidence that over -the -counter DHEA supplements slow the aging process or improve physical performance.

And when individuals misuse these hormones, like athletes taking massive doses of anabolic steroids, the adverse effects are devastating.

Oh, completely.

In adolescents, the excess hormones signal the epiphyseal plates in the bones to close prematurely.

That permanently halts their growth.

And in adult males, flooding the system with exogenous testosterone triggers that negative feedback thermostat we talked about.

The brain senses too much hormone and shuts down the testes.

Leading to drastically decreased sperm production and severe testicular shrinkage, you also see massive disruptions in lipid profiles and profound psychiatric changes, commonly known as roid rage.

Right.

You are overriding an incredibly delicate homeostatic balance and the body fights back.

Which brings us to the final application of this pharmacology, antiandrogens.

Because in certain diseases, the clinical goal is to starve the body of male hormones entirely.

Prostate cancer is a prime example.

Since prostate tumors feed on androgens, we use competitive receptor blockers like flutamide or bicolutamide.

So these drugs travel to the prostate cells, sit directly on the androgen receptors, and physically block testosterone and DHT from binding.

Cutting off the tumor's fuel supply.

We also use targeted therapies for benign prostatic hyperplasia, or BPH, which is a non -cancerous enlargement of the prostate gland.

Right.

We achieve this by targeting that specific local enzyme we discussed earlier, 5 -alpha -reductase.

The enzyme that converts testosterone into the much more potent DHT?

Exactly.

Drugs like finasteride and jutasteride are 5 -alpha -reductase inhibitors.

By disabling that enzyme, they halt the local production of DHT.

So the prostate tissue is suddenly starved of the specific hormonal signal it needs to grow.

Yes.

And that causes the hypertrophy gland to physically shrink, relieving the patient's urinary symptoms.

It is brilliant, targeted molecular engineering, and really, if there is a final thought to take away from all this source material, it's just the sheer power of chemical nuance.

We've seen how tiny structural tweaks like changing a single carbon bond to make an oral pill completely change a hormone's journey through the liver and its side effects.

It really does make you wonder how future molecular engineering might allow us to target diseases like cancer or osteoporosis with absolute precision, achieving incredible therapeutic benefits with zero off -target effects.

From a humble cholesterol molecule to a transdermal patch that can control the human reproductive cycle, it's fascinating.

To our listener prepping for your exam, we hope this deep dive helped clear the muddy waters of Chapter 25's reproductive pharmacology.

You now have the foundational mechanisms, you know the exceptions to the rules, and most importantly, you understand the why behind the clinical warnings.

From everyone here, including the last -minute lecture team, thank you so much for trusting us with your prep and the absolute best of luck on your exam.

You are going to crush it.