The hypothalamus located at the base of the brain secretes gonadotropin releasing hormone GnRH which regulates the anterior pituitary gland to secret FSH Follicle Stimulating Hormone and LH Luteinizing Hormone into the blood which stimulates the production of the ovarian hormones, estrogen and progesterone, which in turn regulate the reproductive process. Oxytocin is released from the posterior pituitary gland.
Non-pregnant and non-lactating sows and gilts display estrus or standing heat on a regular basis throughout the year. The estrous cycle is normally 21 days and is defined as the time between the onset of one estrus to the onset of the next. The cycle length can range from days. Lactation or the nursing stimulus inhibits the estrous cycle and sows will not, as a rule, return to heat until the litter is weaned. Days from weaning until estrus is influenced by such factors as length of lactation, parity, season and nutritional level, but should range from 4 to 7 days.
As estrus or heat approaches, follicles or "blister like" structures form on each ovary. Follicular growth accelerates about 3 days before estrus and is influenced by FSH or follicle stimulating hormone released from the pituitary gland, located at the base of the brain.
A maturing ovum is held within each follicle. Granulosa cells within the follicle secrete estrogen, a hormone, which among other things is responsible for the typical signs of estrus. Ovulation, or release of the ova, is stimulated by LH.
Ovulation occurs about 40 hours after the onset of estrus, but this interval is variable. Several factors can influence ovulation rate or number of ova shed. Sows may ovulate ova while gilts may ovulate ova. Flushing increased energy levels prior to estrus may increase ovulation rate yet may have little effect on the ultimate litter size. The white or maternal breeds generally have a higher ovulation rate.
Crossbred females generally have a higher ovulation rate than either of the parent breeds. The onset and disappearance of estrus and estrus behavior is gradual and there are individual differences among females see Fig. The primary sign , and most reliable sign, of estrus is "standing" while another sow or the boar mounts. Many females will stand for the "back pressure test" when applied by the herdsperson. A higher percentage of females will respond to the "back pressure test" if there is a boar present.
Therefore, use of an intact or a vasectomized boar is an important part of a regular heat detection program. Boars secrete pheromones odors in their salivary glands which elicit the standing reflex of the female.
Mature boars are superior to young boars in stimulating this response. Secondary signs of estrus include: Red, swollen vulva which is usually more pronounced in gilts than in sows. Increased nervous activity. Desire to seek the boar. Loss of appetite. Male-like sexual behavior pursuing, nosing and mounting other females. Change in vocalization grunts and growls. Increase in vaginal mucous thumb check.
Both women and pigs are spontaneous ovulators and continuously cycling [ 21 ]. A comparison of the changes in the reproductive hormones during the reproductive cycles is shown in Figure 1. Both hormonal cycles are under control of the hypothalamic-pituitary-ovarian axis [ 19 , 20 ]. The important differences between the porcine estrous and human menstrual cycles are summarized in Table 1 together with the same parameters in primates and mice, to show the level of similarity compared to these species.
Comparison of reproductive-cycle parameters in women, non-human primates, minipigs and mice. The porcine uterus differs from the human by being bicornuate [ 23 ] Figure 2. The bicornuate elongation of the uterine body into two uterine horns creates a longer distance from the porcine cervix to the entrance of the Fallopian tubes than in women. Comparison of the gross anatomy and epithelium in the genital tract in women and pigs. The porcine uterus differs macroscopically from the human simplex uterus by having bilateral horns bicornuate [ 23 ].
The porcine cervix displays a characteristic feature, not found in women; the cervical pulvini red arrow [ 23 ]. Furthermore, the porcine urethra opens on the ventral surface of the vagina purple arrow creating an urogenital sinus that opens to the outside through the common urogenital orifice [ 23 ]. In women, the urethra and vagina have its own separate openings to the outside [ 19 ].
Otherwise the porcine vagina is similar to the human one [ 92 ]. The human cervix is divided into the ectocervix that protrudes into the vaginal canal and the endocervix, creating the cervical lumen. An example of the local immune system in the female genital tract is shown at the transition between the ecto- and endocervix. The porcine cervix displays a characteristic feature, not found in women; the pulvini cervicales [ 23 ], which are a number of interdigitating prominent solid mucosal folds and protrusions throughout the length of the porcine cervix.
Furthermore, the porcine urethra opens on the ventral surface of the vagina, creating a urogenital sinus that opens to the outside through the common urogenital orifice [ 11 , 14 ]. In women, the urethra and vagina have separate openings [ 19 ]. The vagina in women is approximately 7 cm along the anterior curvature and 9 cm along the posterior curvature [ 25 ].
The Fallopian tubes are 7—14 cm long and 0. Histology is a very important tool in the evaluation of pathological changes in animal models. Therefore, it is important to understand morphological differences between pigs and humans [ 12 ]. Generally, and common for both pigs and humans, the wall of the FGT consists of three layers: the mucosal, the muscular and the outer serosal layers [ 21 ]. The tunica mucosa facing the lumen the endometrium , is built by the inner lamina epithelialis , lamina propria connective tissue and the tela submucosa.
The muscular layer tunica muscularis is built by stratum circulare and stratum longitudinale. The outer tunica serosa the perimetrium , facing the peritoneal and pelvic cavities, is built by a lamina propria and lamina epithelialis [ 21 ].
In the peritoneal cavity the lamina epithelialis of the tunica serosa has a simple squamous epithelium visceral layer of the peritoneum and in the pelvic cavity only loose connective tissue adventitia [ 21 ]. The vagina is the entry site for most sexually transmitted diseases and therefore of great importance when comparing the pig model with humans [ 12 ]. The vaginal lamina epithelialis is made by non-keratinized stratified squamous epithelium and forms longitudinal folds called rugae in both women and pigs [ 12 , 27 ].
The porcine vaginal epithelium undergoes cyclic alterations reaching a maximum thickness in the late proestrus [ 21 ]. The lamina propria consists of vascularized fairly dense connective tissue with no glands or mucosal muscular layer in both pigs and humans [ 21 ].
The vaginal mucosa is moisturized with secretions from the cervix. Cranially the porcine vagina is covered by a typical tunica serosa i. Both tunica serosa and adventitia contain large blood vessels, extensive venous and lymphatic plexuses and numerous nerve bundles and ganglia [ 21 , 28 ]. In women, the vagina is externally covered by adventitia, primarily built with elastic fibers attaching the vagina to the surrounding connective tissues and organs [ 27 ].
Tunica muscularis is also similar for pigs and humans with an inner layer of circularly arranged smooth muscle cells and an outer longitudinal layer, however the pig can have a thin layer within the circular layer with longitudinally arranged fibers [ 21 , 27 ]. Studies have furthermore shown that the porcine vaginal permeability barrier, which is based on the lipid composition and intercellular lipid lamellae in the epithelium, closely resembles that of humans [ 12 ].
The porcine cervix has a thick, muscular wall rich in elastic fibers [ 21 , 23 ], whereas the human only contains small amounts of smooth muscle and therefore mainly consists of dense connective tissue and elastic fibers [ 27 ]. The cervical lamina epithelialis differs between humans and pigs. In women the ectocervix has non-keratinized stratified squamous epithelium and the transformation zone separates it from the endocervix with a simple columnar epithelium [ 27 ].
The porcine cervical epithelium changes between simple columnar, pseudostratified and stratified squamous epithelium, with primarily columnar in diestrus and primarily stratified in estrus [ 21 ]. Common for both species is the simple columnar epithelium, which is mucinous with mucus secreting goblet cells.
The amount of mucus secreted depends on the cycle stage with an increased amount during estrus in pigs and midcycle in women around ovulation. Much of the mucus passes to the vagina. Similarly the epithelium increase in thickness and edema develops during proestrus and estrus [ 21 ].
After ovulation the secretion decreases and the mucus becomes thicker [ 21 ]. The human myometrium tunica muscularis is built by three muscular layers. The thick middle layer stratum vasculare contains many large vessels [ 27 ]. This highly vascularized and well-innervated stratum vasculare is, however, indistinct in the pig [ 21 ]. A tela submucosa, with dense irregular connective tissue, is not present in the uterus in women, where the epithelium with lamina propria lie closely applied to the myometrium [ 27 ].
The epithelium is simple columnar in both women and pigs, but in the pig it increases significantly in height during estrus and can turn into high pseudostratified columnar epithelium [ 21 , 29 ]. The endometrium and structure of the epithelial cells in women are also highly responsive to the hormonal changes and the thickness of the endometrium increases during the late proliferative phase [ 21 , 30 ]. The endometrium in pigs and women can be characterized by two zones or layers; the superficial functional layer stratum functionale and the deeper basal layer stratum basale.
The functional layer undergoes cyclic changes and degenerates partly or completely after pregnancy and estrus in the pig [ 21 ]. In humans, the degenerated tissue is shed during menstruation [ 27 ]. It remains during all cyclic stages and is the source for restoration of the functional layer [ 21 , 27 ]. The uterine epithelium in pigs and women contains both ciliated cells and non-ciliated secretory cells [ 21 ] and branched and coiled endometrial glands that extend into the lamina propria [ 28 ].
In women, these glands are short and straight in the proliferative follicular phase and long and coiled in the secretory luteal phase [ 30 ]. In the porcine endometrium, growth and branching of the glands are stimulated by estrogen and the coiling and copious secretion by progesterone [ 21 , 29 ]. The Fallopian tubes are of special interest in genital Chlamydia research, as they represent the site of infection, where sterilizing pathology develops in women [ 31 ].
The mucosa at the Fallopian tubes is folded into longitudinal folds plicae and the epithelium has non-ciliated secretory cells and ciliated cells that aid in moving the sperm upwards and the ovum downwards. The mucosal plicae in the ampulla have secondary and sometimes tertiary folds creating a complex system of epithelial-lined spaces.
The epithelial lining is made of a single layer of columnar epithelial cells which sometimes is pseudostratified in pigs [ 21 , 32 ]. The epithelium undergoes cyclic changes with the greatest height and ciliation in the late follicular phase, and atrophy together with loss of cilia in the luteal phase [ 30 ]. The Fallopian tube in both pigs and humans can be separated into three parts; the isthmus , which is communicating with the uterus, the ampulla the middle thin walled part , and the infundibulum that has fimbriae to catch the oocyte, when it is released into the peritoneal cavity during ovulation.
The human Fallopian tubes furthermore have an extra compartment called the intramural part. Fertilization will take place in the ampulla in both pigs caudal ampulla and humans [ 21 , 27 ]. The slight anatomical differences in the pig are important to consider when choosing the inoculation route and when evaluating the ascending capacity of an infection. The porcine cervical pulvini make the access from the vagina to the uterus complicated in pigs and should be considered when choosing the inoculation method.
Furthermore, the longer uterine body, in terms of uterine horns, is an important factor for the face validity of the pig model in evaluating ascending infections reaching the Fallopian tubes. In sexually immature conventional pigs inoculation with C. A clear benefit of the porcine anatomy is the human-like prominent Fallopian tubes in the pig that potentially allows studying the tubal pathology induced by a C.
Since the columnar epithelial cells are the target cells for the C. In women the columnar epithelial cells are found together with the transitional cells found in the endocervix and upper FGT [ 34 ]. In the pig, the cervix is dominated by stratified squamous epithelium and columnar cells are only consistently found in the porcine uterus [ 21 , 35 ], and therefore not at the vagino-cervical transition as in women.
It is therefore recommended to inoculate pigs directly into the uterus. The majority of genes expressed in porcine female reproductive tissues are expressed in human FGT as well [ 36 ]. As further eluted to below, pigs share significantly more immune-system related genes and proteins with humans than mice do [ 37 ]. The porcine immune system is well characterized and highly resembles that of humans [ 11 , 36 ], although there are some differences.
One of the differences is the anatomy of the lymph nodes, which are inverted in pigs [ 38 ]. The inverted lymph node structure only affects the lymphocyte migration through the lymph node.
Porcine lymphocytes mainly leave the lymph node through high endothelial venules instead of efferent lymph vessels, as they do in humans [ 21 , 38 , 39 ]. Otherwise the physiology and immunologic reactions of the B and T cell areas in the lymph nodes do not differ [ 21 , 38 ]. Most of the protein mediators of the immune system are present with the same structure and function in humans and pigs and most of the immune cells identified in both species are similar [ 36 , 40 ].
Otherwise the distribution of the different lymphocyte populations in pigs and humans is quite similar [ 11 , 36 , 40 , 42 ] as summarized in Table 2. The major histocompatibility complex MHC system in pigs, called the swine leukocyte antigen SLA system is very similar to the human leukocyte antigen system, in terms of polymorphic loci, haplotypes and differentiated expression on different cell populations [ 11 , 43 ].
The expression and frequency of immunoglobulins are quite similar Table 2 except that IgD has not been demonstrated in pigs. Circulating IgA is mostly bone marrow derived and monomeric in humans [ 49 ], while circulatory IgA in pigs is half dimeric IgA and half monomeric IgA [ 50 ]. The dimeric proportion of circulating IgA in the pig is, however, primarily derived from the intestinal synthesis and lymph.
Due to the hepatic pIgR-mediated transcytosis of polymeric IgA pIgA to the bile, the dimeric IgA is thought to be relatively short-lived in the circulation [ 50 ].
The hepatic polymeric immunoglobulin receptor pIgR -mediated transcytosis of pIgA happens in both humans and pigs [ 50 ]. In women, IgA2 is known to be the predominant isotype subclass in the genital secretions [ 51 ] while this distinction cannot be made in the porcine FGT secretions. It has been shown that the porcine TLR system is very similar to that of humans [ 41 ].
In terms of cytokines such as the neutrophil chemokine IL-8, the coding gene carried by humans and pigs is an ortholog [ 41 ]. The genital mucosal immune responses are of specific importance when using the pig as a model of human genital C. The genital immune response is challenged in the sense that it has to tolerate sperm, the semi-allogeneic conceptus and the commensal vaginal flora, while it must mount defense responses against sexually transmitted pathogens in order to eliminate them [ 52 ].
The genital immune system consists of both innate and adaptive factors. The innate system is primarily built by the epithelial barrier, the production of antimicrobial agents and cytokines by the epithelial cells and the innate immune cells [ 40 , 53 ]. Both innate and adaptive humoral mediators and immune cells in the genital immune system are regulated by progesterone and estradiol and therefore fluctuate through the menstrual or estrous cycles [ 53 ].
The epithelial cells in the FGT with interconnecting tight junctions play an important role in the immune protection by providing a strong physical barrier, transporting antibodies to the mucosal surface, secreting antibacterial compounds and by recruiting immune cells [ 54 , 55 ]. The sex hormones regulate the structural changes in the epithelium during the cycle. Under the influence of estrogen, the integrity and strength of tight junctions in the epithelial barrier, is significantly weakened in women [ 54 , 56 ].
The secretion of antimicrobial compounds is also suppressed during the midcycle in women [ 53 , 57 ]. To preserve an intact protective barrier, the genital mucosal immune response is often non-inflammatory to avoid inflammation-mediated injuries usually caused by phagocytic activity and complement activation [ 55 ]. Most of the antigens in the FGT are therefore met with mucosal tolerance [ 55 ].
Thus, the genital mucosa lacks an organized center to disseminate antigen-stimulated B and T lymphocytes to the distinct sites of the mucosa. However, lymphoid aggregates LA are present in the female genital mucosa of both pigs [ 35 ] and humans [ 55 ] and leukocytes are dispersed throughout the mucosa of the FGT [ 58 ] as illustrated in Figure 2. The LA are located in the basal layer of the endometrium close to the base of the uterine epithelial glands and built by a core of B cells surrounded by T cells and an outer layer of macrophages [ 58 ].
Aggregates of NK cells can also be found in the endometrium but they are placed in close contact with the luminal epithelium [ 58 ]. The leukocytes present in the FGT covers macrophages, dendritic cells, NK cells, neutrophils, B cells and T cells [ 53 , 59 , 60 ] with lymphocytes being the predominant immune cell type in both pigs and women [ 35 , 61 , 62 ].
The number of immune cells and the size of LA are under strong hormonal influence and fluctuate through the cycle [ 55 , 58 ] as summarized in Table 3. Fluctuations in immune cells and antibody levels in the female genital tract during the hormonal cycles. Both women and pigs show regional differences in the hormonal regulation of the genital immune system. The antibody fluctuations seem similar in women and pigs but the influx of neutrophils during estrus is specific for pigs.
It should be noted that the porcine studies are rather old and only including few animals. The immunoglobulins found in the FGT either have been locally produced by subepithelial plasma cells, or derived from the circulation [ 63 ]. Although IgG producing plasma cells can be found in the FGT [ 64 ], genital IgG is mainly derived from the circulation [ 63 , 65 - 67 ] and transported to the mucosal surface by mechanisms such as passive leakage, paracellular diffusion or receptor-mediated transport [ 63 , 65 ].
When produced locally, the polymeric secretory IgA sIgA is actively transported across the mucosal epithelia cells by the polymeric immunoglobulin receptor pIgR [ 65 , 66 ]. The secretion of sIgA primarily takes place in the cervix due to the focused pIgR localization in the cervix in women [ 72 ].
The pIgR is also expressed in the uterus, but to a lesser extent and in variable levels due to hormonal regulation [ 55 ]. Usually, sIgA is the predominant isotype found in mucosal secretions, such as the intestinal fluid. The FGT humoral immune response is under strong hormonal influence during the menstrual or estrous cycle [ 57 , 74 ]. The cyclic fluctuations in the antibody levels are compared in Table 3. The information on cycle-dependent variations in the level of antibodies in pigs is sparse and more knowledge is needed within this area.
The most important immunological difference with potential influence on Chlamydia models is the slightly different influx of immune cells in the porcine FGT, characterized by an increase in neutrophils during estrus. It should be kept in mind that this increased innate response during estrus could influence the establishment of infection. In women, the vaginal microflora is known to play an important role in the innate genital immune system by inhibiting the colonization of pathogens [ 76 , 77 ].
Lactobacilli and other lactic acid producing bacteria are particularly associated with equilibrium in the vaginal flora and inhibition of the growth of pathogens [ 76 , 78 , 79 ].
However, the species composition can be very different between individuals and during the menstrual cycle [ 52 , 76 , 79 ]. In women, the lactic acid producing bacteria play an important role by contributing to an acidic environment with a pH of 3.
In healthy pigs the vaginal flora has been characterized by culture dependent methods and was found to include both aerobic and anaerobic bacteria with the most prominent being the following: Streptococcus spp. Streptococcus spp. Furthermore, we found that the vaginal flora was not dominated by lactobacillus as in humans. Lactobacillaceae constituted on average 3. An old study showed that the FGT mean pH in estrus in pigs is 7. The primary aim of this review was to compare the female reproductive physiology of humans and pigs, however, as a concluding section, we found it important to highlight where the minipig shows significant differences to the commonly used murine model in Chlamydia research.
Similar comparisons of humans and mice has been done elsewhere [ 4 , 82 , 83 ], and only main points will be included here. The reproductive cycle is significantly shorter in mice, having a 4—5 day cycle due to the lack of progesterone-producing corpora lutea and thereby a luteal phase, if no coital stimulation occurs [ 84 ].
Anatomically, the murine uterus is bicornuate and much smaller than the porcine and human ones [ 83 ]. Histologically, the vagina displays keratinized squamous epithelium during estrus, whereas porcine and human epithelium does not keratinize [ 83 ].
Within the immune system, the composition of circulating leukocytes is significantly different with a lower percentage of neutrophils and a corresponding higher abundance of lymphocytes in mice compared to pigs and humans [ 82 ].
Furthermore, murine macrophages produce nitric oxide NO in response to stimulation with LPS, whereas human and porcine macrophages do not [ 36 ]. There is also a great difference in the expression of cytokines such as IL-8, a strong neutrophil chemokine expressed in pigs and humans, but not in mice.
In the hip, however, there are some differences in the gluteal muscles. Quiz: How are the gluteal muscles of the pig different than the gluteal muscles of the human? See p. Pigs have all of the same thoracic and abdominal organs as humans. There are small differences in a few organs. Liver — the human liver has four lobes: right, left, caudate and quadrate. The fetal pig liver has five lobes: right lateral, right central, left central, left lateral, and caudate. Intestines — there is a significant difference in the structure of the fetal pig colon compared to the human colon.
The pig colon is spiral. Adrenal glands — In the fetal pig, the adrenal glands are found near the aorta towards the cephalic end of the kidneys, instead of on top of the kidneys as is the case in humans. Quiz: Like humans, the adrenal glands of the fetal pig are retroperitoneal.
What other abdominal organs are retroperitoneal? Stomach, spleen, bile duct system, small intestines, kidneys, bladder, etc. Thymus — the thymus is found in the same areas in pigs as in humans. However, it is much larger than most students1 expect. This is not a difference of pigs from other mammals.
All mammals have a large enormous thymus gland during the fetal stage. It gradually shrinks, relative to the rest of the body, throughout life. Quiz : Humans have three lobes in the right lung, two lobes in the left lung. How many lobes are there in the lungs of the fetal pig? Pericardium, vena cava, esophagus, phrenic nerve, etc.
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