#351 ‒ Male fertility: optimizing reproductive health, diagnosing and treating infertility, and navigating testosterone replacement therapy | Paul Turek, M.D.

The incredibly complex and hostile journey sperm must take to fertilize an egg [3:00]

Explain what’s involved in conception through the lens of sperm 

• Peter wonders how much of a challenge this is
• Obviously there’s an enormous evolutionary pressure for this to go as easily as possible
• But what is actually involved?
• What happens for a sperm to fuse with an egg?
• What are all the things that are standing in its way, so to speak?

Paul explains, “Reproduction is an incredibly highly-evolved, million-year process, and remarkably conserved among mammalian species, even among land species and water species of animals.” 

Vaginas, cervixes, uteruses

• The question is, why is it so much work for a sperm to get into the vagina? 
• And then have to go through a cervix
• The immune system in the uterus is very active, because there’s a hole in the woman to the abdomen, so it has to be highly protected
• Sperm have to go through the uterus, so there’s a 10-inch, 12-inch swim
  • Which is equivalent to about a 20-mile swim for a human 
  • And they do that in minutes, which is crazy
• It’s an interesting challenge that nature has kept in place for a million years
• Paul really respects evolution, and it is why we’re here: to eat, sleep, reproduce

Basically with ejaculation, the penis is shaped to fit into the cervix 

• Everyone wonders, is it getting to the right spot? 
• It’s also interesting that the semen is coagulated, and then it liquefies
  • And that’s because there’s a lot of species of lower phyla that they have to leave as soon as they have sex, otherwise they’ll get killed (like praying mantises and black widow spiders)
  • Ejaculates in humans are sticky ‒  Paul has no idea why, no evolutionary explanation for this
• A lot of men think they’re having trouble placing things
• Paul doesn’t worry about it because the cervix and the penis expand to form a seal

Challenges sperm face and the numbers that make it   

• 1 – Sperm have to go through a crypt (a channel), and only a few sperm make it
• So 100 million sperm may start out, maybe 5 million make it through the first barrier, which is the cervical barrier
• 2 – The vaginal fluid is acidic (pH 5)
  • Semen is pH 7
• It’s all buffered as a hostile environment, so it has to get out of there quickly
• As soon as the sperm liquefies (there’s sugars in there), they go through the cervical path
• So 5 million will make it
• 1 out of 20 makes it through the cervix
• Then 100 make it to the fallopian tube, and then 1 will make it to the egg 
• These numbers were found by studies done in the 50s of women who had sex before hysterectomies
  • Then different parts of the reproductive tract were swabbed 
  • These young women had hysterectomies for different reasons, not infertile
• This is the basis for our move to technology, from 5 million moving sperm when we start doing inseminations versus sex
  • Those are based on the numbers of sperm that reach the uterus
• Everyone thought the vanguard sperm wins
  • It’s the Phelps sperm that’s going to make it
• There’s a company out of Boston called Arex Life Sciences, and they’ve discovered that sperm work in phalanxes 

Disclosure: Paul is consulting for Arex Biosciences

• Because the immune system is so vibrant in the uterus, the first round of sperm gets through the cervix and typically absorbs the immune system, secretes Fc receptor

Peter asks, “We’ve referred to the immune system a couple of times now… What is the barrier?”

• The full immune response: T cells, B cells, and antibodies
• There’s also a mucus plug that exists for 28 days a month to prevent anything from going through, because it’s a hole into the woman’s body, and peritonitis is severe

⇒ The cervical mucus thins, and that’s to let sperm through for 2 days a month

• It’s an incredibly detailed, perfectly-orchestrated system

It looks like the first round of sperm get through the cervix, get into the uterus, and they get demolished like a Roman phalanx 

• Maybe a second round goes through and they get demolished
• They’re secreting the FCR receptor on the immunoglobulin, because that’s what female antibodies bind to

We don’t know how many phalanxes go through, but then it’s like a run up the middle, and then eventually a couple of sperm make it, and the immune system is deactivated and they get there (it’s wild)

• That can be measured now, and there’s actually going to be an assay available to look at whether you’re doing this
  • They’re calling it a sperm cycle 
  • Almost like ovulation, spermulation
  • It’s an hour and a half cycle when the phalanx is working, sperm are deactivating the immune system, and then maybe they don’t
  • There are jaculates (which is a group of sperm) and some of which do this well and some of which don’t

⇒ That can be a whole reason for infertility ‒ if you’re not able to deactivate the system, you’re not going to be able to get through, because the immune system is active 

Summary of the numbers of sperm 

• 100 million ejaculated at the cervix
• 5 million get through the cervix, into the uterus
• 100-500 get to the fallopian tube
• 1 gets to the egg

Paul jokes about why you need so many sperm 

• The classic answer he used to give is they don’t like to ask for directions
• But these numbers illustrate why

How sperm are made: meiosis, genetic variation, and the continuous renewal influenced by environmental factors  [9:00]

• An important consideration for sperm is it can only have half the genetic information contained within all other cells in the man’s body

When does that take place? 

• The testicle makes sperm
• It takes about 60-70 days, and it’s a process called meiosis
• So in a car assembly line, cars are mass produced, and you want it all to be the same
• In meiosis (which is unlike mitosis), you want things to be different and to be a little easy-peasy
  • You get what’s called recombination, and that’s the source of evolution
  • The chromosomes blend in a different way and separate in a different way

⇒ Through that process, you get half the number of chromosomes, which is required to join the other half 

• But it’s not always the same half

Funny story about when Peter took the MCAT 

• Peter had to take the MCAT before doing any of the pre-med stuff, because he had studied engineering before deciding he wanted to do medicine
• He didn’t want to spend 2 years preparing
  • 1 year taking the post-bac and then the MCAT
• He decided to just wing it and take the MCAT, having never taken a biology class since high school (he took freshman biology)
• He’s studying his heart out for this, and the physics and chemistry are fine, but the biology is killing him
• He bought this cheap study guide (he didn’t want to splurge for the official study guide)
• And every time he encountered the word meiosis and mitosis, he assumed it was a spelling mistake because he bought a knockoff book (he thought it was just mitosis)
• Finally, on the night before the exam, he realized they were 2 totally different things
  • There’s a big difference
• That realization might have gotten him into med school, because he thinks he barely got at 10 on the biology section
  • It’s hard to get into a good med school if you get below that

To this day, Peter gets such a chuckle out of the confusion of the nomenclature  

⇒ Mitosis happens when cells are dividing in our body, where they’re trying to create a perfect replica of the entire suite of DNA while meiosis only occurs in the creation of an egg or a sperm 

Are women born with all of their eggs? 

• 5 million eggs at conception
• 1 million eggs at birth
• You basically ovulate 1000 eggs in your lifetime
  • 1 a month
  • But you actually produce 10 a month, so you lose 10 eggs every month
• By the time you’re 45, you’re out of eggs
• There’s a lot of waste
• The eggs are stuck in a stage of perpetual space, and they get older but they don’t evolve 
• They mature at the time they are asked to

But sperm are constantly renewed 

Peter asks, “Is that just a mass space problem? Because the testes, if we did the same thing women did, would we just have to have an enormous set of testes?”

Paul jokes, “Why do you think out of the box like that?”

• He’s not sure
• There’s a whole issue of what’s the source of human evolution
• It’s really sperm because they are constantly dividing, constantly influenced by the environment
  • And they’re throwing off mutations and epigenetic changes

What’s most interesting for Paul for this talk is that whatever happens in sperm, happens to offspring  

• It’s transgenerational

Does that mean that the father is more likely to pass on environmental stressors than the mother?  

• Probably
• That’s definitely been shown

⇒ The sperm is the actual cell

Where do sperm get the little tail from, and what is the other part of the cocktail? 

“One of the most magnificent transformations of a cell in the body is the making of a sperm.”‒ Paul Turek

• It starts with a spermatogonial stem cell, which looks like other cells
• That spermatogonial stem cell is actually the first and the bottom of a tube
  • There’s 12 stages of spermatogenesis
• That cell is remarkable; it’s actually the human male embryonic stem cell
• Paul has a patent on that cell, because if you take that cell and you put it in a niche environment like an embryonic stem cell, it’ll become embryonic almost like it can become multipotent
  • You can form tumors, and you can form bone, mesoderm, ectoderm, and endoderm
  • You can do all three layers of the body with that adult spermatogonial stem cell

Peter asks “Is there any other cell in the body that is capable of that?”

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