Reproduction in mammals is a highly complex biological process. The critical importance of reproduction to propagation of species required the natural evolution of various strategies that vary considerably across species. Regardless of species, a dialogue between the developing conceptus (embryo-fetus and associated placental membranes) and maternal uterus must be established during the peri-implantation period. The uterus must provide a microenvironment that supports growth and development of the conceptus and is receptive to implantation. During the same period, the conceptus must provide its pregnancy recognition signaling to sustain the functional life of corpora lutea for production of progesterone which is essential for implantation and placentation; critical events for successful pregnancy. However, it is within the peri-implantation period that most embryonic deaths occur due to deficiencies attributed to uterine functions or to the failure of the conceptus to develop appropriately, signal pregnancy recognition and/or undergo implantation and placentation. The challenge is to understand the complexity of key mechanisms that are characteristic of successful reproduction in humans and animals and to use that knowledge to enhance fertility and reproductive health or to establish acceptable methods for control of fertility.

Uterine receptivity to implantation of blastocysts in mammals.

In dogs, the termination of the 3-10-month obligate anoestrus involves selection of a cohort of LH-sensitive follicles, presumably from a wave of dominant small antral follicles that would otherwise undergo atresia. The number and size of such follicles appears to increase, especially during the last 50 days of anoestrus when the already elevated concentrations of FSH become further elevated. The final selection and eventual terminal development of these follicles is caused by an increased frequency of high-amplitude LH pulses at the end of anoestrus. Concomitant increases in FSH are typically small or negligible. High concentrations of FSH in anoestrus are likely to be important in maintaining, if not stimulating, overlapping waves of dominant follicles throughout anoestrus, their expression of aromatase activity and basal oestradiol secretion sufficient to suppress LH by negative feedback. An attractive hypothesis is that late anoestrus increases in LH-stimulate synthesis of precursor androgen for already available FSH-dependent aromatase. After 7 or more days of elevated LH, and perhaps 2-5 days of semi-autonomous growth, with maximal oestradiol production reached, follicle capacity to further increase oestradiol becomes limited and excess progesterone becomes increasingly secreted. The pre-ovulatory LH surge and oestrus onset are then triggered - often synchronously and in concert with the terminal maturation of the follicles - by central effects of the large decrease in the oestrogen to progestin ratio. Follicular endocrine and paracrine events during and following the LH surge are likely similar to those reported for other species. The prolonged luteal phase lengths of 55-75 days in non-pregnant bitches bracket the 64 +/- 1 day in pregnancy and represent a genetically programmed luteal cell lifespan approximating gestation length as occurs in the luteal phase of hysterectomized animals of most polyoestrous artiodactyls and rodents. The 30-40-day slow regression after day 20 to 30 involves periodic cell death, diminution in cell size, low levels of apoptosis and minimal or modest involvement of endogenous prostaglandin F (PGF) production. The canine corpus luteum (CL) is dependent on both LH and prolactin as stimulating luteotrophins by day 15, and as required luteotrophins by days 20-25, if not earlier. Thereafter, both luteotrophins likely have cellular mechanisms of action similar to those reported for other species. Progesterone secretion during pregnancy is greatly enhanced by characteristic, and probably relaxin-stimulated, increases in prolactin concentration starting at or after day 25, and persisting to term. Near term, foetoplacental maturation results in the placental release of large, luteolytic amounts of PGF for 1-2 days pre-partum. Pre-partum luteolysis, like that induced by exogenous prostaglandin, likely involves a cascade enhanced by the removal of progesterone inhibition of PGF release and some degree of intra-luteal PGF synthesis. That a likely twofold or greater increase in progesterone production by the CL of pregnancy does not result in significantly higher serum progesterone than in non-pregnant metoestrus relates to several biological changes, including a large increase in plasma volume of distribution, increased metabolism of progesterone by increased uterine, placental and mammary masses and increased liver clearance and excretion of progesterone and progesterone metabolite. Anoestrus length and ovarian cycle intervals, variable within and among bitches, are likely affected by neuroendocrine components of an endogenous circannual cycle, albeit only photo-entrained in the Basenji breed. This may be modified by the prior luteal phase, exposure to oestrus female pheromones and as yet unknown mechanisms that likely operate via inhibitory opioidergic and/or stimulatory dopaminergic hypothalamic pathways affecting late anoestrus increases in LH.

Endocrinologic control of normal canine ovarian function.

Pyometra is a common disease in dogs and cats. Hormones and opportunistic bacteria are fundamental in the development, with progesterone playing a key role. The disease should be suspected in intact bitches and queens presenting with illness, and particularly if within 4 months after estrus. Early diagnosis and treatment are vital to increase chances of survival as endotoxemia and sepsis often are induced. Typical clinical signs include vaginal discharge, depression, anorexia, polyuria and polydipsia, fever and gastrointestinal disturbances. Surgical ovariohysterectomy is the safest and most effective treatment. For breeding animals with less severe illness, purely medical treatments alternatives are possible.

Pyometra in Small Animals.

Infectious diseases of the dog and cat

Citation Ott TL, Gifford CA. Effects of early conceptus signals on circulating immune cells: lessons from domestic ruminants. Am J Reprod Immunol 2010



While there are few similarities between mechanisms for extending corpus luteum (CL) function during early pregnancy in ruminants and primates, there is increasing evidence that conceptus-immune crosstalk in ruminants and primates affects the function of circulating immune cells at the very earliest stages of pregnancy. Most notable are changes in immune cell phenotypes with increased numbers of cells exhibiting the T regulatory phenotype and suppression of Th1 cytokines that promote tolerance to paternal alloantigens. Until recently, interferon τ produced by the ruminant trophectoderm was thought to act exclusively on the uterine endometrium; however, it is now clear that this unique embryonic interferon escapes the uterus and alters gene expression in the CL and in peripheral blood leukocytes (PBL). In fact, a large number of interferon-stimulated genes are now known to be increased during early pregnancy in PBL. What is not known is how this conceptus-immune system cross-talk affects maternal immune status outside the reproductive tract. It is attractive to hypothesize that some of these effects are designed to counter-balance progesterone-induced immunosuppression so as not to place the dam at a greater risk of infection on top of the tremendous stresses already induced by pregnancy. Furthermore, recent evidence suggests that pregnancy induced changes in peripheral immune cells may aid in orchestrating establishment of pregnancy. Existing evidence points toward a greater convergence of systemic immune responses to early pregnancy signaling between ruminants and primates.

K. Verstegen-Onclin

Papers

Mucometra, cystic endometrial hyperplasia, and pyometra in the bitch: advances in treatment and assessment of future reproductive success.

Endocrinology of pregnancy in the dog: a review.

Canine and feline pregnancy loss due to viral and non-infectious causes: A review

Efficacy of four density gradient separation media to remove erythrocytes and nonviable sperm from canine semen.