Thread by @AbudBakri

TESTOSTERONE and XY chromosomes are NOT enough to make someone a "normal" man

You need:

- XY chromosomes
- SRY gene
- sensitive androgen receptors
- functioning LH receptors
- 5 alpha reductase
- normal aromatase
- 17β-Hydroxysteroid dehydrogenase III
+ more

Anything missing can lead to DSD (differences in sex development)

Let’s examine the step by step process and what happens when things go off course 👇🧵

disclaimer: this is not a commentary on who is or isn't a man

This is just a step by step journey of all the things that need to go right for "normal" masculine development, from conception to birth to puberty

the concept of intersex is complex, and researching this blew my mind

DSD, sometimes referred to as intersex is often distinctly different than transgender

ok lets begin 👇

Step 1:

XY chromosomes

there are 23 pairs of chromosomes

The last pair are the sex chromosomes

Females are XX

Males are XY

Simple, right?

I wish…

Step 2: SRY gene

The key gene that leads to sexual differentiation is the SRY gene on the Y chromosome

The presence of this gene lead to masculinization, including the development of testicles and secondary male characteristics

But here's where it gets messy...

Technically, everyone starts out as a female as an embryo with "ovaries" but the SRY gene program leads to the transformation of "ovaries" into testicles and their descent out of the body into the scrotum

Sometimes the SRY gene is missing or inactive on Y chromosome, rendering it inactive

This leads to Sywer syndrome or  XY complete gonadal dysgenesis

Born XY, but without testicles

Appear female externally but have problems with puberty, end up needing progesterone/estrogen to enhance female characteristics

A karyotype on these patient would be confusing

Now the OPPOSITE can also happen

The SRY gene can MOVE from the Y chromosome to the X chromosome

This leads to a patient who is XX but has testicles thanks to the SRY gene

This is called XX male or de la Chapelle syndrome

These patients are normal males externally but are  infertile with small testicles. Hard to diagnose

In the past the Olympics would test for SRY genes to prove that only females were competing but this became controversial and was stopped after the 2000 games

A lot of false positives and confusing results

Step 3: Normal androgen receptor

The androgen receptor is what allows testosterone to induce its biological effect on gene transcription

Androgen receptor insensitivity is when someone has XY and SRY intact, but the receptor to testosterone is NOT working

If the receptor is functioning, the body can't fully experience the effects of testosterone, regardless of how high it is

1 of every 20,000 to 30,000 males has a 46,XX karyotype with the SRY gene, so its possible someone reading this is a case 🧐

The androgen receptor is what allows testosterone to induce its biological effect on gene transcription

There is a spectrum of androgen receptor insensitivity, ranging from mild to complete

Mild (MAIS) can lead to decreased male secondary characteristics while complete (CAIS) leads to looking externally like a female, despite sky high testosterone levels

Side note: There is a spectrum of androgen receptor sensitivity even among normal males, with some males being more sensitivity than others

This explains the very large variation in male testosterone and the difficulty in diagnosing symptoms of low testosterone

Some races are on average more sensitive

Step 4: 5 alpha reductase

Even with XY, SRY, normal androgen receptor, you NEED DHT

5 alpha reductase (5ar) converts testosterone into the more active DHT, which is ESSENTIAL for virilization

DHT in utero is essential for the development of male characteristics
5ar deficiency leads to DSD

These patients are born looking as females externally because not enough DHT was present during development to cause external male characteristics

This is what is being speculated that certain olympic athletes have, but there is NO CONFIRMATION of this

During puberty, the surge in testosterone leads to more masculinization as this is able to slightly overcome the lack of DHT

DHT is not active in the muscles, so these patients would look female but with more male musculature given they have sufficient testosterone levels

In fact, in a remote village in the Dominican Republic called Las Salinas there are many cases of this condition

They are initially raised as girls, but around age 12 they develop male characteristics. They are known locally as guabidós or guevedoces

Side note: This is story provided the idea for the drug Finasteride, which was developed by Merck

Step 5: Normal LH receptor

The brain makes LH which tells the testicles to make testosterone

There is a rare condition called Leydig cell hypoplasia where the LH receptor is not functioning

These patients partially or fully underdeveloped genitalia and infertility

Step 6: Normal steroid conversion enzyme

The first of which is Aromatase

It converts testosterone into estrogen. However two problems can arise:

1. XX females, too LOW aromatase end up with not enough estrogen and too much testosterone, leading to enlarged clitoris

2. XY males, too HIGH aromatase can lead to high estrogen and more female secondary characteristics such as gynecomastia

Another important enzyme is 17β-hydroxysteroid dehydrogenase III

This converts Androstenedione into testosterone in adrenals and testicles. Low levels can lead to lower testosterone and difficulties with secondary male characteristics

The steroid interplay from the adrenal glands to gonads is fascinating and many things can go wrong, such as congenital adrenal hyperplasia, but that affects XX females

Miscellaneous

On top of the six steps above, there can be other anomalies that occur that affect sexual development, such as Klienfelters XXY, where there is an extra x chromosome

Additionally, rarely some patients have mosaicism, where part of their body is XX and another part is XY

These patients sometimes have ovaries AND testicles, leading to Ovotesticular syndrome

As you can see, so many things can go wrong on the development of the typical masculine phenotype and its truly a miracle that the majority of men have normal male development

This was not meant to be comprehensive and there are more examples of DSD, which I will be posting about in coming days

Normally these cases are extremely RARE but because of their involvement in sports and the current cultural climate, more people are aware and discuss them

Understanding the nuances and complexities surrounding DSD can help better respect and address these patients

Please let me know if there are other threads on similar topics you would like to see!

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Thanks!