Of Pregnancy and Progesterone

Female mammals, like those of many other creatures, are not permanently fertile. Instead, they go through regular cycles, ovulating at intervals under the control of hormonal signals produced by the pituitary gland and the ovaries. In humans, this manifests as the menstrual cycle, but this is a relatively unusual feature of our species.

Whether or not other mammals menstruate may depend on your exact definition of the term. Chimpanzees certainly do (and, indeed, rarely experience menopause), and it's present to a variable extent in other apes and Old World monkeys. In New World monkeys it's microscopic and it's completely absent in lemurs. At least some bats menstruate, as do sengis (elephant shrews) and, so far as we know, just one species of rodent.

For everything else, there are oestrus cycles.

The primary difference between the two is that, in mammals experiencing oestrus, the uterine lining is simply absorbed back into the body rather than being shed, with or without blood. (Why we, and other menstruating mammals, don't do this is unclear, as it has some downsides even beyond the obvious). It's also often the case that females are only willing to mate when they are in the fertile part of their oestrus cycle ("in heat"), although we are by no means the only species to ignore that rule. Other than this, however, there is a degree of similarity, with the two processes being controlled by essentially the same hormonal signals.

The full process is complex, with multiple stages and feedback loops, but the two primary hormones that control the process are oestradiol and progesterone. ("Oestrogen", if you're wondering, is a term for a general type of hormone, of which oestradiol is the most important in mammals). Both are found not only in all mammals that we've bothered to check, but in many other vertebrates as well, most likely first appearing well before our ancestors started breathing air instead of water and quite possibly even before we evolved backbones. 

Exactly what the two hormones do varies between vertebrate groups, and goes beyond maintaining the menstrual/oestrus cycles even in mammals, but those are undeniably an important element of their function. However, if maintaining those cycles is important, it's also crucial to stop them when an animal gets pregnant.

Here, progesterone is the key. During the regular cycle, it promotes the growth of the uterine lining, or endometrium, ready for an embryo to implant. (I'm ignoring monotremes here, where the progesterone is definitely doing something, but it's less clear exactly what). If the animal does not become pregnant, progesterone levels fall and the endometrium is either shed or absorbed, depending on the species. But if she does, progesterone levels remain high, allowing pregnancy to continue without interruption.

The structure responsible for this is the corpus luteum. This is formed from the ovarian follicle that released the egg cell. It is effectively a temporary endocrine gland, pumping out progesterone (and, to a lesser extent, some other hormones) to keep the endometrium primed, as well as initiating other changes in brain chemistry, relaxation of the uterus, and the immune system. 

If ovulation results in pregnancy, then the corpus luteum remains functioning up until birth. The reasons for this vary between mammalian species. In humans and horses, the outer layer of the embryo, and later on, the placenta, produces a hormone called hCG that tells the corpus luteum to keep going - this is the hormone that pregnancy tests usually look for. Other mammals may have different mechanisms, but the end result is the same.

On the other hand, if the female mammal does not become pregnant, then the corpus luteum shrinks and stops functioning, kicking off the next part of the cycle. It becomes a "corpus albicans" - essentially a scar that may eventually be absorbed back into the body. Except... this doesn't necessarily happen straight away. In fact, it's quite common for the corpus luteum to continue functioning even when the animal isn't pregnant. This delays the cycle, pushing back the next opportunity to get pregnant. Which, especially in the case of an animal with a short breeding season, might mean that you have to skip a year.

The fact that this is nonetheless common even in perfectly healthy animals means that there has to be some reason behind it. If so, there might be a pattern to how long the corpus luteum remains active after a failure to conceive. Is it longer in some species than in others and, if so, do those species have something else in common?

This recently published review tries to answer that question, looking at studies in 72 different species of mammal from across the evolutionary family tree. The species examined fell broadly into six groups: primates, ungulates, carnivorans, marsupials, rodents/lagomorphs, and xenarthrans. Obviously, this isn't everything with bats being the most obvious omission, but with things like shrews and elephants also being left out, presumably because the reviewers couldn't find any studies with the relevant information.

Nonetheless, it's a broad analysis, including mammals with a wide range of different lifestyles, body sizes, and evolutionary histories: the sample includes hamsters, humans, koalas, jaguars, and beluga whales. The variation in how long corpora lutea continued functioning after pregnancy was huge; just one day for some of the rodents, but over three months in some of the carnivores. Putting it all together, three trends emerged.

The main one that the authors discuss is that the longer a pregnancy would normally last in a given species, the longer the corpus luteum tends to survive even when the animal does not become pregnant. Marsupials are an extreme example here, because their pregnancies are very short indeed, with most development of their young occurring in the pouch after birth. It turns out that while marsupials continue to produce progesterone for slightly longer than we'd expect after a failure to mate, they still follow the overall trend, despite having quite different mechanisms for destroying the corpus luteum than placental mammals do.

The authors suggest that this may be due to a form of evolutionary inertia. That is, because pregnancy lasts longer in these animals, and they need to keep producing progesterone for longer to do that, it's harder to switch off when it isn't needed. There is, perhaps, a balance here between the need to prepare for a real pregnancy and the need to quickly reset when you don't have one.

The second trend in the dataset is closely related to this; in six species, the corpus luteum remained functional for over 180 days in non-pregnant females. The six included three kinds of bear, plus roe deer, walruses, and a sea lion. Significantly, all of them share a characteristic none of the other species in the sample did: they all exhibit embryonic diapause.

This is a process by which pregnancy pauses for an extended period. The developing embryo simply stops growing, entering a sort of suspended animation for a while before starting up again. The usual purpose of this is to ensure that young are born immediately prior to the next breeding season, so that pregnancy lasts just under twelve months regardless of the size of the animal. In sea lions and walruses, for example, it ensures that they don't have to haul out on land twice a year and can get birthing and breeding done in one go. Even a six-month-long boost of progesterone isn't going to interfere with that, and, again, it may be a side-effect of needing to ensure that the uterus can hold a baby for an extended period.

Finally, the review showed that species with distinct breeding seasons, where any delay to the opportunity to breed again could prevent it altogether for the year, tend to have corpora lutea that last longer than those in species that mate all year round, where it wouldn't matter. Which is the exact opposite of what you would expect - the bigger a problem it would be, the more likely it is to happen.

They almost gloss over that, unable to come up with an explanation. Perhaps it will make more sense when we eventually get a better understanding of what's going on at a molecular level in non-human mammals. For now, all we can say is that there is still more to learn.

[Photo from the US Fish and Wildlife Service, in the public domain.]