A paper that came out on August 20th in PNAS suggests a factor in semen that could induce ovulation. The idea that this could happen isn’t new, but identification of the factor that might do it certainly is. Ratto et al (2012) contend that they have found The Magical Semen Ingredient That Makes the Ladies Swoon (Then Ovulate), and it is Nerve Growth Factor, or NGF. (Full disclosure: I didn’t notice until I was halfway through writing this post that a collaborator of mine, Roger Pierson, is a co-author on this paper.)
Much of the online conversation I’ve seen about this paper begins with an implication that the research was on or related to humans, then a quick switcheroo to reveal they were, in fact, talking about llamas.
Which are an admittedly cool species, one which my generation of Sesame Street watchers no doubt remembers from this song:
And that same generation now reads to their own children Llama Llama Red Pajama, Llama Llama Mad at Mama, and the rest of the Llama Llama series by Anna Dewdney (we have nearly all, and my daughter can recite most from memory). It’s fun to say, it rhymes with a lot of stuff, and they can spit at you. What’s not to love?
But, well, llamas aren’t humans. So I’m going to explain why this distinction is important, why this research is still really cool, and the reasons I can see that make NGF interesting in humans after all.
Bet you can’t make me ovulate!
Some animals ovulate with the act of intercourse – either the physical act stimulates it, or there is some factor in the semen that signals that it’s time to pop out that egg. Such an animal is called an induced ovulator, and this group includes llamas, the rest of the camelids (camels, alpacas), but also cats, minks, voles, and a few others.
The other kind of ovulator is the spontaneous ovulator. This is far more common and this is how we primates ovulate. Spontaneous ovulation is when ovulation is triggered spontaneously and internally via the suite of hormones that nourish and mature egg follicles. This is why you often see a distinction in the infertility literature between “spontaneous” cycles that occur naturally, and “stimulated” cycles that are brought about using fertility drugs (which are just synthetic versions of the hormones we produce).
So there is room for an external mechanism to influence ovulation, even in spontaneous ovulators. We have scores of papers showing that energetic stressors (particularly not eating enough) can delay or cease ovulation. Issues with insulin, thyroid hormone or androgens (take your pick, it’s a murky mechanism) can make too many follicles ripen at once then struggle to ovulate, leading to a diagnosis of polycystic ovarian syndrome (PCOS).
But that’s not quite the same thing as The Magical Semen Ingredient That Makes the Ladies Swoon (Then Ovulate).
Oh, the things NGF could do that are good for you
In llamas, the discovery of NGF and its abilities supports the hypothesis many have held that there is something in semen whose specific purpose is to stimulate ovulation… among induced ovulators. And the discovery that it’s NGF, and not some newer, whacked-out chemokine that had never before been identified, suggests we are looking at a fairly conserved (evolutionarily old and passed on among many modern species) feature.
This alone is striking and important.
What else does NGF do, and why would this be the trigger for ovulation in llamas and their fellow induced ovulators? NGF has a lot of other jobs, mostly related to in utero development of the central and peripheral nervous system, and neuroendocrine or immune tasks once born (Levi-Montalcini, 1987).
But NGF has also already been examined for a possible role in ovarian function. And its role is quite interesting!
NGF appears to facilitate ovulation. In the hour leading up to egg release, trkA (tyrosine kinase receptor) and NGF gene expression increase in the ovary (Mayerhofer et al., 1996). What seems to happen is that NGF activates trkA receptors in a way that eventually leads to a degradation of the follicular wall, which aids in follicular rupture from the ovary. Breaking down the ovary’s last arguments about why the egg shouldn’t get to go out that night, NGF is like a feisty aunt that encourages troublemaking.
If this aunt spoils the egg too much, or doesn’t see enough of her, problems can arise. In one sample of women seeking assisted reproductive technology, NGF was found to be higher among women with diminished ovarian reserve, but lower among those with PCOS (Buyuk and Seifer, 2008). Yet a different study found NGF associated with PCOS in a mouse model, and high NGF in women with PCOS (Dissen et al., 2009). Both studies measured NGF in follicular fluid in women during assisted cycles to try to get pregnant: the Buyuk and Seifer (2008) collected during egg retrieval, but the Dissen et al (2009) doesn’t say when (it would make sense to assume the same time-point, though).
Different results despite a similar sample population and sampling methods? It might mean we don’t understand the mechanism that well yet. It could also point to the fact that PCOS is a hugely variable syndrome, likely with multiple origins, and so you could potentially get different samples with different NGF concentrations by chance and still have both studies be meaningful. Either way, NGF seems like a very important factor to consider in PCOS, since in some PCOS women we are seeing maturation of many follicles but no ovulation.
So how else might NGF be stimulating ovulation?
Maybe NGF stimulates luteinizing hormone!
This is the pathway the authors of this paper propose (Ratto et al 2012). Rather than NGF acting in some paracrine (cell to cell) manner, they contend NGF zooms over to the anterior pituitary (in your brain), which makes luteinizing hormone (LH), and the LH then zips to the ovary and tells it to put the finishing touches on the egg and let it go.
If we’re talking about locally produced (by the woman) NGF, this all makes sense to me because it would be part of her own spontaneous cycle regulation. Here’s what I don’t get. If semen-derived NGF were to induce ovulation it probably wouldn’t happen in time for that ejaculate’s sperm to have a follicle to fertilize. So this would really only work if someone was having sex regularly so that an earlier episode could prime a later fertilization. In a promiscuous species, which is somewhere in our ancestry, this seems like a terrible idea. You might be wasting your mating effort ripening a female’s eggs so that some other schmo gets to fertilize them! This is why to me, semen-derived NGF is currently in the “may not help, but doesn’t hurt” category for now when it comes to spontaneous ovulators like us.
Maybe NGF stimulates mast cells!
Or perhaps the mechanism is an inflammatory one? NGF activates mast cells, which degranulate (release histamine) and start the inflammatory process. Mast cells in the endometrium produce tryptase which induces angiogenesis and neovascularization (making new blood vessels). But endometrial mast cells are the most activated just before menstruation (Salamonsen and Lathbury, 2000). In fact, tryptase activates matrix metalloproteinases (MMPs), which break stuff down, which is why they are so important to menstruation. However, some think histamine could be a paracrine signal involved in decidualization and implantation (Noskova et al., 2006). So… NGF could facilitate menstruation if timed towards the end of the cycle, or implantation, if timed during the implantation window.
Llama Llama Ovarian Drama
Intra-ovarian NGF is an important component of the mechanism of ovulation in spontaneous ovulators, and seminal NGF is important for ovulation in induced ovulators. It’s entirely possible the seminal NGF is also important to women's reproductive function in some way. My big questions – and I really hope someone does follow-up work on this – are what is a physiologically relevant concentration of NGF in spontaneous ovulators (so, how much you need to actually do anything), and what produces variation in intra-ovarian NGF? I’m very curious whether gonadotropins, hormones, or external factors influence any of this stuff. Considering intra- and extra-ovarian sources of variation in ovulation just made lady parts that much more interesting!