Wednesday, September 2, 2015

Don’t Disrespect The Dizygotic

Biology concepts – dizygotic twins, assisted reproductive therapies, in vitro fertilization, oogenesis, follicles stimulation, hormones, body mass index

In the 2015 movie Spy, Melissa McCarthy looks like a
housewife, but gets to prove herself as an international
agent. Sometimes the things that look boring really
aren’t. Fraternal twins (dizygotic) are really much more
interesting than identical twins (monozygotic).
Sometimes the thing that seems least interesting has some hidden facets that make it the most riveting thing around. Superman was a geek as Clark Kent. Sure, he was still tall and muscular, but put on the glasses and everyone just saw something boring. As Superman, he turned out to be a rather interesting character. The lesson, don't dismiss what seems uninteresting.

If you consider monozygotic and dizygotic twins, the identical version appears to be more interesting on the face. Two people that look exactly alike? That’s so cool. But on the other hand, their just a mistake of embryologic division, and that happens to lesser or greater degrees all the time.

It’s amazing that that something as difficult as making another person can ever go right, but what if it happened twice – at the same time in the same uterus?! Dizygotic (fraternal) twins are the truly amazing feat, and I’m going to prove it to you.

The rates of monozygotic (MZ) twinning are the same all over the world, but dizygotic (di = two, and zygote = fertilized eggs, DZ) twinning rates vary from place to place. What’s more, DZ twin rates are exploding worldwide. In the US, they are up from 1 in 58 births in 1980 to 1 in 35 births in 2008. And no, it’s not just because of assisted reproductive therapies (in vitro fertilization and things like that).

African women have more DZ twins, so it probably has a genetic component, but tall women have more DZ twins too - so do older women, overweight women, and women who smoked before pregnancy. Just what the heck is going on here?

Let’s take a look and see what a female would have to do to give her the best chance of having DZ twins. First things first - to have DZ twins, a women must release more than one egg in one fertility cycle - duh. But what controls how many eggs are released? One factor is race and the genetics that go often travel along with race.

DZ twinning is so common in west Africa that is has
been put into their mythology. The first twins supposedly
came about because a farmer was killing monkeys, so the
monkey deities put two babies in his wife’s belly. To keep
them safe and healthy, he had to stop killing monkeys.
Twins are reported to carry the fate of the family, good or
bad, so they are treated especially well.
Worldwide, the rate of DZ twinning is about 13/1000 live births. But Nigerian women have twins in 60 of 1000 live births, because they have the highest basal levels of follicle stimulating hormone (FSH). The ovaries are under some intense hormonal controls, including the FSH that stimulates a follicle to start developing and to release an egg. With more FSH, it is more likely that more than one egg will be released.

Interestingly, Nigerians are different in another subtle way. European and American women have about the same FSH levels with women who twinned having just a bit more than women that don’t have twins. In contrast, while all Nigerian women have much higher FSH levels, the ones that were more likely to have twins had much higher levels of FSH than those that were not as likely to have twins. It seems that something more might be involved, though I don't know what it is.

On the other hand, DZ twins in East Asia are exceedingly rare. Japanese women are the least likely to have DZ twins, just under 2 births of every 1000 in Japan are twins. And low and behold, Japanese women have the lowest basal serum FSH levels.

But the genetic link to DZ twins doesn’t stop at race and locality. DZ twins can run in families, while MZ twins are pretty random. Even more perplexing, if any woman has a set of DZ twins, she becomes 4x more likely than the control population to have another set of DZ twins. It turns out that having DZ twins creates a permanent bump in her FSH levels, so the release of multiple eggs is more likely after having had a set of twins.

A disputed idea about twinning in different parts of the
world has be to relate it to ecology. R type species have
more offspring but invest less in them because the harsh
environment means more will not survive. K type species
have fewer offspring but invest more in their nurturing.
Under Philipe Rushton’s theory, Africans have more twins
because they act more like an R type species. I reject this;
humans re a single species.
FSH is certainly a big factor in DZ twinning, and we will see more of it below, but there are other genetic factors that can play a role in creating DZ twins. One protein, growth differentiation factor-9 (GDF9) seems to have a dual role in fertility. A primary function for this protein is to make sure that follicle and egg development proceed normally. GDF9 prepares and maintains the ovary cells and their functions so that an egg has the best chance of developing and being released.

But on the other hand, it seems that reducing GDF9 function can promote DZ twinning. A 2006 study showed that there can be several mutations in the GF9 gene, some in the upstream region that controls the expression level and some in the coding region that mcould create a shorter protein. These mutations are found more often in women that have had DZ twins.

Just having a mutation doesn’t mean that there will be less of the protein – sometimes a mutation can make the protein more efficient at its job, or a mutation in the upstream region can lead to a higher expression level. But in the case of GDF9 mutations, they seem to reduce expression.

A 2014 study showed that women (and sheep) that were heterozygotic for a mutation that eliminated GDF9 expression had both, 1) lower serum GDF9 levels, and 2) more DZ twins. Being heterozygotic means that had one copy of the regular gene and one of the mutant, nonfunctioning gene, so they had 50% of the normal blood levels of GDF9. So, a protein crucial for making sure good eggs are developed and released can also regulate how many eggs will be released.

Cow’s milk has high IGF-1 levels, so drinking milk may help
to promote DZ twinning. I don’t think cat really cares about
that; it just wants a drink without being kicked out
of it’s nine lives.
Genetics is fine, but let's talk about the weird reasons for having DZ twins. Women over 35 are 4x more likely to have DZ twins than a 20 year old mom. Yet, as women age, their fecundity (fertility) is reduced. It’s back to FSH we go; older women have higher levels of FSH. They are less likely overall to get pregnant but more likely to have twins. What gives?

It turns out that FSH levels are generally stable over the reproductive years of a woman (monthly pulses excluded), but after she hits about 35 or so, the levels start to rise. After menopause, the levels of FSH are very high in all women, so it seems that an small increase in basal FSH promotes twinning and fecundity, but a larger rise leads to infertility and is a sign of menopause. It’s when FSH levels have started to rise, but before they go too high that older women are more likely to have DZ twins.

See, I told you that DZ twins were more interesting than MZ twins – and we’re just getting started. It has been proven that tall women are more likely to have DZ twins as well. It just so happens that the countries that have the tallest women, inside and outside Africa, also have the highest DZ twinning rates.

No one should smoke, period. But most certainly don’t smoke
when pregnant. It leads to increased fetal heart rate,
miscarriage, and reduce birth weight. However, a study in 2010
indicated that smoking before pregnancy can
increase the chance of having DZ twins. I have no idea why.
Do taller women have more FSH? No. But the answer is related to FSH. There is a protein called insulin-like growth factor-1 (IGF-1). This protein is important for long bone growth, both in length and width. Tall women have longer bones, so they do have higher levels of IGF-1.

A secondary function of IGF-1 is to make the ovary more sensitive to FSH. If two women have the same levels of FSH, but one has a higher level of IGF-1, then she is more likely to have multiple ovulations in a single cycle. Hence, tall women are more likely to have natural DZ twins – so are cows. Cows that have more twins have 2x the level of IGF-1.

But there is another part, one that makes less sense as of now. In women that undergo IVF and have two embryos transferred to the uterus, the ones that are more than 1. 74 m (5 ft. 8 in.) tall are much more likely to have both embryos implant, develop and to deliver DZ twins. This isn’t associated with multiple ovulation, so it isn’t related to ovary sensitivity to FSH through increased IGF-1. Do taller women have uteruses of greater volume so that there is more room for two developing fetuses? I don’t know, ask a tall woman's twins if they felt less cramped.

Body Mass Index is supposedly a measure of healthy weight
(mass (kg)/ height (m)2). A BMI of over 30 or so means you’re
obese. BUT – it doesn’t take body type or muscle mass into
account. At his body building best Arnold Schwarzenegger
would have been considered morbidly obese.
The IGF-1 explanation might work for parts of another phenomenon as well. Women with a BMI (body mass index) of over 30 tend to have natural DZ twins at a higher rate. Other studies have shown that overweight women do have higher levels of IGF-1. But on the flip side of this, overweight women also have lower levels of FSH. So there is evidence to explain why high BMI women have more twins and evidence to say it shouldn’t be happening.

And the same study that showed that double embryo transfer in tall women resulted in more twins didn’t show the same thing for high BMI women.  If one wanted to make an evolutionary argument, you could say that being overweight is a signal that the environment is good enough to support more babies, so more DZ twins might result – but that’s just speculation.

The sextuplets from John and Kate + Eight are now 11 years
old. Their show is off the air, which is great for the kids, but
there are more just like it. So, we have learned today that if you
want DZ twins or multiples - be a tall, overweight, more than
35 year old African woman who used to smoke – or have
multiple embryos implanted like Kate Gosselin.
Finally, assisted reproductive therapies (ART) like IVF have increased the rate of DZ twinning. If you implant 6-8 embryos, some women are going to have twins or higher multiples. The TV is chock full of reality shows about quads and quints and sextuplets. BUT – ART can’t explain the size of the increase in DZ twinning; there just aren’t that many women having IVF. Can you think of another reason?

It’s not smoking (see image above); smoking rates, even among teenage girls are going down. Any other reason come to mind? Yep, obesity rates are skyrocketing. This may be the biggest single reason for the great leap in DZ twinning (along with increased access to prenatal healthcare that may preserve more DZ twin pregnancies).

Next week – let’s dive into DZ twinning. We saw for the past few weeks that there are many kinds of MZ twins (mosaic, parasitic, conjoined, vanished, polar bodysex discordant) – is the same true for DZ twins? You bet.

Simpson, C., Robertson, D., Al-Musawi, S., Heath, D., McNatty, K., Ritter, L., Mottershead, D., Gilchrist, R., Harrison, C., & Stanton, P. (2014). Aberrant GDF9 Expression and Activation Are Associated With Common Human Ovarian Disorders The Journal of Clinical Endocrinology & Metabolism, 99 (4) DOI: 10.1210/jc.2013-3949

Palmer, J., Zhao, Z., Hoekstra, C., Hayward, N., Webb, P., Whiteman, D., Martin, N., Boomsma, D., Duffy, D., & Montgomery, G. (2006). Novel Variants in Growth Differentiation Factor 9 in Mothers of Dizygotic Twins The Journal of Clinical Endocrinology & Metabolism, 91 (11), 4713-4716 DOI: 10.1210/jc.2006-0970

Steinman G (2006). Mechanisms of twinning: VIII. Maternal height, insulinlike growth factor and twinning rate. The Journal of reproductive medicine, 51 (9), 694-8 PMID: 17039697

Aladashvili-Chikvaidze N, Kristesashvili J, & Gegechkori M (2015). Types of reproductive disorders in underweight and overweight young females and correlations of respective hormonal changes with BMI. Iranian journal of reproductive medicine, 13 (3), 135-40 PMID: 26000003

Hoekstra, C., Willemsen, G., van Beijsterveldt, C., Lambalk, C., Montgomery, G., & Boomsma, D. (2010). Body composition, smoking, and spontaneous dizygotic twinning Fertility and Sterility, 93 (3), 885-893 DOI: 10.1016/j.fertnstert.2008.10.012

Groeneveld, E., Lambers, M., Stakelbeek, M., Mooij, T., van den Belt-Dusebout, A., Heymans, M., Schats, R., Hompes, P., Hoek, A., Burger, C., van Leeuwen, F., Lambalk, C., & , . (2012). Factors associated with dizygotic twinning after IVF treatment with double embryo transfer Human Reproduction, 27 (10), 2966-2970 DOI: 10.1093/humrep/des258

For more information or classroom act ivities, see:

Dizygotic twins –

Body Mass Index –

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