Open access peer-reviewed chapter - ONLINE FIRST
Abstract
Progesterone (P4), a steroid hormone, is widely recognized for its vital function in maintaining pregnancy across various animal species. Its functions extend beyond pregnancy management, encompassing the determination of pregnancy, optimal reproductive timing, anticipation of parturition, scheduling of elective cesarean sections, and identification of conditions like growth hormone disorders, insulin-dependent diabetes, and infertility. Its versatility extends to involvement in bone marrow trophication, stress response assessment, and neuroprotection following traumatic brain injuries or fetal hypoxia. Although the aforementioned are mostly directed toward females, it is important to note that progesterone is also used clinically in males. Monitoring blood progesterone levels in animals is essential in both healthy and pathological states, as emphasized in this chapter.
Keywords
- progesterone
- endocrinology
- diagnosis
- small animals
- large animals
1. Introduction
Despite nearly a century following its discovery by a group of researchers at the University of Rochester, there are still aspects of progesterone’s role in the animals that make it in their bodies that remain to be understood. Undoubtedly, the absence of it would result in the absence of offspring, since it plays a crucial role in female cyclicity, preparing the uterus for gestation and ensuring its maintenance. It is classified as a progestogen, which is a kind of steroid hormone and is considered the most significant hormone in this category. In general, its functions are comparable in domestic animals, encompassing both reproductive and mammary gland aspects, as well as metabolic processes, since it is recognized as a neurosteroid.
Progesterone (P4) is produced by the corpus luteum, which forms following the release of the dominant follicle. Following that, several components including both large and tiny thecal cells, fibroblasts, and vascular elements will form a genuine endocrine gland that is accountable for producing progesterone and other compounds, depending on the specific species.
Alternatively, depending on the species, the placenta, which is the link between the mother and fetus, can sustain pregnancy by releasing several hormones, including the mentioned hormone.
Due to the wide range of reproductive and non-reproductive scenarios in which progesterone plays a role, it is crucial to provide a clear description of the specific instances in which this hormone might be utilized for diagnostic reasons. The objective of this chapter is to provide doctors with a realistic technique to assist them in assessing progesterone levels.
2. Progesterone’s diagnostic reach in domestic carnivores
For domestic carnivores, prompt assessment of progesterone (P4) levels is essential for diagnosing conditions and making clinical decisions [1]. This includes the use of serum or plasma P4 measurements as diagnostic aids in various reproductive disorders such as pyometra, pseudopregnancy, ovarian remnant syndrome, hypoluteinism, ovarian cysts, or any form of disturbed estrus cycle such as silent estrus, split heat, or even delayed puberty/primary or secondary anestrus.
Additionally, the applications of P4 measurements extend to feline pregnancy diagnosis and pregnancy monitoring in both dogs and cats. Confirming P4 drops before parturition is essential for cesarean section (C-section) timing protocols [2]. Moreover, P4 is extensively used for ovulation determination and, consequently optimal breeding, the abrupt increase in P4 concentration during ovulation being a more reliable reference point when deciding on the “fertile window” when compared to the preovulatory peak LH concentration [3].
Progesterone’s implications extend beyond the reproductive system, with research indicating its involvement in various areas such as neurodegenerative states and demyelination [4, 5, 6], as well as its association with conditions like dog hyperadrenocorticism [7] or adrenocortical tumors [8]. Additionally, progesterone has been linked to other metabolic influences, including its relationship with insulin activity and diabetes mellitus [9].
2.1 Estrus phase diagnosis and breeding management
In female dogs, the incipient luteinization process of granulosa cells prior to ovulation will translate into a noticeable rise in peripheral P4 concentrations. This particularity empowers us to use P4 as a diagnostic tool even before the start of the metestrus. Therefore, P4 levels under 1–2 ng/mL may be indicative of anestrus [10] or early to even persistent proestrus [11]. Further dynamics will prove a rapid elevation above 1 ng/mL during the preovulatory LH surge, with P4 plasma concentrations on the day of LH reaching 2.95 ± 1.2 ng/mL [12]. Subsequently, it undergoes further rapid escalation, either immediately or following a pause of 1–3 days, reaching levels of 10–25 ng/mL by day 10 of the cycle, typically occurring at or shortly after the end of estrus, post-ovulation [13].
In addition to clinical examination, vaginal cytology, vaginoscopy, LH assays, and ovarian ultrasound, P4 measurements were considered among the foremost methods utilized for monitoring the estrus cycle and diagnosing ovulation. This became essential for the utilization of cryopreserved material, enhancing assisted reproductive technology (ART) applications in small animal medicine.
However, P4 is able to significantly increase the diagnostic accuracy for ovulation prediction, and a standard value interval is hardly considered due to method and individual variability [14, 15]. Several groups compared different techniques for P4 analysis the ovulation range being cited as between 2.76 and 10 ng/mL [1, 10, 13, 14, 15, 16, 17, 18, 19, 20].
In cats, P4 levels can also confirm ovulation. Breeding management recommendations suggest that serum P4 values exceeding 2 ng/mL at 1–2 weeks after mating indicate the presence of a luteal body [21]. When ovulation is pharmacologically induced, the success of this intervention can be checked by P4 measurements at 3–5 days distance [22].
2.2 Disturbed cycles
The abnormal cyclicity in the dog may refer to the failure of exhibiting estrus or to the unexpected duration of one of the phases including the interestrus interval. The first scenario may refer to primary or secondary anestrus. The age of puberty in female dogs’ ranges from 6 to 14 months, with a diagnosis of primary anestrus potentially warranted if estrus has not occurred by 24 months of age [11]. The term secondary anestrus indicates that the patient has experienced at least one estrus cycle in the past but is currently unable to enter heat for several months (typically 12 months) [23]. Both conditions need to be distinguished from silent heat, missed heat, or drug-induced anestrus. Current recommendations suggest using P4 serum analysis for this purpose, with concentrations exceeding 2 ng/mL indicating that ovulation is imminent or has occurred within the last 2 months [24]. Moreover, recent approaches suggest that monthly P4 testing can be conducted to ascertain whether an unnoticed estrus has taken place in a supposedly non-cycling female dog [25]. In non-spayed felines, primary anestrus is usually ruled out similarly to the bitch taking into account any possible sexual development abnormality along with probable iatrogenic or environmental factors that may postpone puberty. On the other hand, for the secondary anestrus, P4 may actually reveal some important aspects such as lack of estrous due to a spontaneous ovulation not followed by pregnancy. In this case cyclicity will cease and P4 will remain high for 40–45 days [25].
Prolonged or persistent proestrus/estrus is another functional problem that may be detected in the bitch by the help of P4 monitorization. Even if the average duration for the proestrus period is still considered to be of 9 days, some females may exhibit signs of proestrus for up to 28 days until advancing to estrus [25]. Therefore, in suspected persistent estrus/proestrus cases, it is advisable to conduct vaginal cytology and progesterone testing [26]. Progressive cornification should match the increase in P4. On the contrary, if P4 reassessment proves no luteinization after 30 days of vaginal keratinization, that may indicate the evolution of an ovarian pathology with subsequent estrogenic stimulation and ovulation failure. Therefore, P4 may also guide the clinician in the diagnosis of follicular cysts or ovarian neoplasia.
Conversely, shorter interestrus intervals in bitches may be associated with two diverse situations: split heat or abbreviated metestrus/anestrus. The first stated condition will be clinically described as a female dog who exhibits estrus symptoms for a limited period of time without ovulating, followed by a silent interval and subsequent resumption of heat symptoms. Females experiencing a shortened metestrus and/or anestrus are those that enter heat again less than 4 months after an estrus period with confirmed ovulation. In terms of P4 testing the two situations may be differentiated, as during split-heat P4 does not rise above 2.0 ng/mL initially and this fact will be marked by the disappearance of estrus clinical signs and vaginal smear cornification [26]. The shortened luteal phase will be characterized by a consistent increase in P4 associated with a faster return to estrus.
Another rare cycle abnormality (1.2%) which usually evolves with a shorter interestrus interval is anovulation [27]. Primary cause of the latter, in dogs, is related to the failure of the ovary to deliver enough estrogen to elicit an LH surge [26] which will be equivalent to the insufficient mechanical stimulation during mating in the cat which will similarly produce insufficient LH release [28]. In both species the absence of ovulation can be highlighted through P4 serum determination, specific values being reported as under 2 ng/mL.
2.3 Detection of residual ovarian tissue
The ovarian remnant syndrome is a relatively frequent issue in veterinary practice, being reported as a complication in 17–43% ovariohysterectomy cases [29]. The detection of residual ovarian tissue can involve presumptive diagnosis through clinical observations, complemented by additional assessments such as vaginal cytology. Ultrasonography can also be employed as a diagnostic tool in this context. When considering slightly more invasive methods for diagnosing ovarian remnant syndrome, measuring concentrations of estradiol and P4, both before and after stimulation with gonadotropin-releasing hormone (GnRH) or human chorionic gonadotropin (hCG), as well as assessing luteinizing hormone (LH) or anti-Müllerian hormone (AMH) [30, 31], encompass the practical diagnostic possibilities. Lately a protocol combining P4 and AMH on the same serum sample proved to increase sensitivity for ovarian remnant syndrome diagnosis in dogs [29]. Even without stimulation, P4 alone can still be helpful in dogs, as progesterone concentrations may remain elevated for approximately 4 months out of a 12-month period, indicating the presence of functional luteal tissue. However, in queens, evaluating P4 may reliably detect ovarian tissue only if ovulation was induced.
2.4 Ovarian cysts
Functional ovarian cysts come in two types: follicular and luteal cysts. Furthermore, nonfollicular cysts may develop from the surface or subsurface epithelium and mesonephric tubules of the dog’s ovary [32]. As primary diagnosis is achieved through clinical and ultrasonographical findings, definitory differential assessment of the cyst type relies on ovarian steroid hormone concentrations or histopathology. Follicular cysts typically induce a characteristic clinical buildup owing to their estrogenic influence. However, luteal cysts have the potential to extend the interestrus period, without any other clinical evidence. A diagnosis approach was proposed for these cases based on demonstrating the prolonged secretion of serum progesterone (>2 to 5 ng/mL) during 9- or 10-week period [33]. Moreover, a more invasive approach was also described based on the levels of oestradiol-17ß and progesterone concentration in the cystic fluid [34].
2.5 Progesterone dependent disorders of the reproductive tract
As a consequence of high progesterone levels associated with the normal luteal phase, various reproductive disorders may develop in both dogs and cats, including cystic endometrial hyperplasia, pyometra, pseudopregnancy, and mammary gland hyperplasia. For most of the stated pathological entities, P4 assessments may slightly increase diagnosis accuracy as it has the power to conclude on the estrus cycle phase, knowing the specificity of these disorders in relation to the metestrus. However, some particular pyometra cases including stump pyometra may benefit even more from P4 determination [35, 36]. Moreover, if medical treatment is attempted for pyometra, some authors consider serum P4 monitorization as being crucial in confirming the return to baseline levels after treatment initiation [37].
2.6 Pregnancy diagnosis and monitoring
P4 levels in female dogs remain elevated, whether they are pregnant or experiencing pseudopregnancy. Thus, by relying solely on progesterone levels, one cannot confirm pregnancy. However, monitoring progesterone is crucial in cases of complicated pregnancies, history of resorptions, abortions, or stillbirths. Additionally, determining the timing for parturition or C-sections in bitches can benefit from progesterone checks, as P4 levels typically fall 48–36 hours before parturition [24]. This differs for cats, as their progesterone concentrations decrease as parturition approaches but may not return to basal levels until after birth [38]. Consequently, progesterone levels cannot reliably predict parturition in cats. Conversely, P4 may provide late pregnancy diagnosis in felines. High P4 levels after 45 days of pregnancy, which coincides with the end of the possible pseudopregnancy, which may render a false positive, will prove placental progesterone production and therefore gestation [39]. However, this technique does not offer any information regarding the vitality of the embryo/fetus [40].
To effectively manage pregnancy, it is advisable to regularly do clinical examinations, ultrasounds, and P4 tests to detect any underlying conditions that might potentially impact the pregnancy. In cats, luteal insufficiency does not raise as many concerns as in dogs according to the different endocrine physiology. On the other hand, hypoluteoidism is considered among the potential explanations for pregnancy loss in dogs that undergo resorption, abortion, or premature whelping [24]. The consensus among most authors is that diagnosing hypoluteoidism in dogs involves ruling out all other potential causes of pregnancy loss, particularly infectious factors like
2.7 Parturition timing and elective C-section
When no data is available according to the LH peak or ovulation timing, together with ultrasonographical measurements, P4 assessments are important for parturition prediction or C-section scheduling. For a P4 level of 1 ng/mL, whelps are typically within 18–24 h; if P4 is below 1 ng/mL, early stages of whelp have either begun or will begin within 18 h [45].
C-section has been regarded as safe for both the bitch and the litter when progesterone levels decrease below 2 ng/mL [46]. Based on other studies, the threshold was set to 1.47 ng/mL [47]. Another approach stated that it is more important for the female to be within 48 hours of the spontaneous onset of parturition than to have a P4 level below 2 ng/mL for the safety of a programmed C-section [48]. Nevertheless, determining the stage of pregnancy often relies on P4 assessments meant to accurately pinpoint the day of the LH peak or ovulation, expecting normal parturition to take place 65 days ±1 or 63 days ±1 after the stated events [13]. Alternatively, serial vaginal cytology may be employed to ascertain the beginning of metestrus, considering that a scheduled C-section can be safely performed around 57 days after the start of the luteal phase [48].
2.8 Beyond reproduction
The impact of elevated progesterone levels in various metabolic disorders has been thoroughly examined, and its involvement in regulating glycemic levels has already been established [49]. Modern research highlighted that elevated P4 and P4-regulated growth hormone overexpression during metestrus or pregnancy pose a significant risk factor for the development of diabetes mellitus, particularly in older female dogs [9]. Therefore, P4 serum assessments were recommended as valuable tools in the initial screening of the entire diabetic female dog [9]. This approach allows the practitioner to understand the relationship between P4 stimulation and impaired insulin activity, thereby guiding him toward an appropriate intervention to improve the success of diabetes management.
Another application for P4 testing refers to advanced investigations related to occult hyperadrenocorticism, which was described as the situation in which history and clinical findings indicate hypercortisolism, but all stimulation tests fall into the accepted reference ranges [7]. The release of progesterone, along with 17-α-hydroxy-progesterone or other sex hormone or cortisol precursors, may inhibit pituitary adrenocorticotropic hormone secretion and lead to the degeneration of healthy adrenocortical tissue [50]. Analogously, serum P4 was proved to be useful for adrenocortical tumor diagnosis [8]. In such cases, progesterone-secreting adrenal tumors can cause specific hypercortisolism tests to yield negative results despite the presence of typical clinical signs and the tumor itself.
Progesterone has been associated with various neurodegenerative processes [4, 51]. However, investigations into distemper virus-infected dogs revealed no significance in either P4 serum levels or cerebrospinal fluid P4 [5]. Nevertheless, there was a significant decrease in cerebellum progesterone concentration [5], sparking future interest in this topic concerning various neurological conditions.
3. Progesterone’s diagnostic reach in ruminants
3.1 Establishing the stage of sexual cycle in ruminants
In cattle, a decreasing trend of progesterone (P4) (in milk and in blood plasma) was observed before ovulation: in milk from <15 ng/mL (97.7 ± 17.8 hours before ovulation) to <5 ng/mL (79.7 ± 11.2 hours before ovulation), <2 ng/mL (70.7 ± 16.8 hours before ovulation) and in plasma from <4 ng/mL (90.5 ± 19.6 hours before ovulation) to <2 ng/mL (75.0 ± 12.2 hours before ovulation). Due to the wide range in the timing of progesterone concentrations dropping in relation to ovulation in different animals, it is recommended that progesterone monitoring is always accompanied by a transrectal ultrasound examination to determine the time of ovulation [52]. The onset of the luteal phase is represented by the increase in milk P4 concentration from <5 ng/mL to values > 5 ng/mL, and the luteal phase lasts as long as the P4 concentration is >5 ng/mL [53].
In goats, following the analysis of progesterone concentration in matched samples of feces and blood, a stunning similarity was observed between the patterns of progesterone variation throughout the sexual cycle. However, there are two differences: a slight delay in the evolution of progesterone in feces compared to plasma (1–2 days), and the values of progesterone concentration in feces are much higher compared to those in plasma (41.87 ± 2.16 ng/g vs. 0.36 ± 0.04 ng/mL in follicular phase and 241.31 ± 17 ng/g vs. 8.29 ± 0.56 ng/mL in the mid-luteal phase). This study is an experimental model, and the observed results can be used in the case of wild ruminants in which it is much easier to determine the stage of the sexual cycle by determining progesterone following the collection of feces than by blood samples [54]. In dairy goats, fecal progesterone concentration testing may offer an alternate technique for diagnosing early pregnancy and predicting estrus and parturition. Consequently, there was a noticeable decrease in the fecal progesterone levels 3 days before estrus was observed (until 396.9 ± 59.8 ng/g from 2957.6 ± 352.0 ng/g 5 days before estrus). The measurement of fecal progesterone levels 19–20 days after mating enables a precise diagnosis of pregnancy (1044.7 ng/g). The fecal progesterone profile appears to have increased gradually between weeks 7 and 14 of pregnancy, peaked between weeks 15 and 21, and then rapidly declined to start 5 to 6 days prepartum (5212.8 ± 463.6 ng/g), with a notable reduction occurring 1–2 days prepartum (3884.3 ± 576.0 ng/g). No significant correlation was observed between the concentration of progesterone from the feces and the number of kids born [55].
In general, buffalo ovulations are limited to P4 levels in milk and serum, which range from 0.1 to 2.9 ng/mL and 0.1 to 0.4 ng/mL, respectively. The mid-ovarian cycle P4 peak levels in milk and serum were found to vary between 6.7–17.8 ng/mL and 2.6–8.5 ng/mL, respectively. It was determined that in regularly monitored buffalo, a dramatic drop in milk P4 level to less than 2.9 ng/mL may serve as a reliable signal for when ovulation occurs [56].
3.2 Predicting pregnancy loss
In cattle, in order to determine if an early loss of pregnancy occurs, the plasma concentrations of progesterone and Pregnancy Specific Protein B (PSPB) can be measured on days 29–45 post-mating, the P4 variation being the decisive one. Thus, if the PSPB value is 0.6–1.1 ng/mL, but P4 < 2 ng/mL, the percentage of pregnancy loss in dairy cattle is higher than in the case of the same PSPB concentration, but with the level of P4 greater than 4 ng/mL [57].
3.3 Pregnancy diagnosis
In cattle, serum or milk progesterone can represent tools for early diagnosis of pregnancy, but with a precision that is not 100%. Samples are collected on days 21 and 24 post-artificial insemination, and if at least one sample has a low progesterone value, the female is non-pregnant. In other words, if the concentration of progesterone is high in both samples, the cow should be pregnant [58]. Pregnant animals have fecal progesterone concentrations of more than 50 ng/g on days 18–24 after artificial insemination or estrus, suggesting that feces can be used as an alternate for plasma and milk in measuring progesterone for the purpose of pregnancy diagnosis in heifers and cows [59].
According to a recent study, the approximately 7-day antepartum P4 and IGF-1 levels could be considered diagnostic markers for the following gestation [60].
In sheep, indication of pregnancy was established at a plasma progesterone level in ewes of ≥1.75 ng/mL [61]. Plasma progesterone concentration at day 18 post-mating is a reliable indication of fertilization success since it remains elevated in pregnant ewes while decreasing in ewes who did not conceive [62].
As in the case of ewes, it seems that an early pregnancy diagnosis can be made in buffaloes on the concentration of progesterone that will be higher in pregnant females than in non-pregnant ones on the 18th day after mating [63]. It seems that P4 concentrations in the serum and milk of pregnant buffalo varied from 2.0 to 8.5 ng/mL and 3.1 to 18.6 ng/mL, respectively, whereas the P4 levels in serum and milk of non-pregnant animals varied from 0.1 to 8.5 ng/mL and 0.1 to 19.9 ng/mL, respectively [56].
3.4 Diagnosis of luteal deficiency
In cattle, Intense metabolism, steroid hormone clearance from excessive milk production, heat stress, and other variables can all be implicated in low luteal activity, making it difficult or impossible to make an etiologic diagnosis [64]. Clinical diagnosis can be made using plasma or milk P4 concentrations in correlation with ovarian brightness (B)-mode ultrasonography or color-flow Doppler ultrasonography in order to monitories the luteal vascularization [65]. Up to day 40 of gestation, pregnant cows’ plasma P4 concentrations, and luteal body blood flow have been found to positively correlate [66]. While an earlier (<7 days) or delayed (>11 days) onset of luteal activity post-artificial insemination has been linked to a lower pregnancy rate, there is a clear correlation between the rise in plasma P4 concentrations post-ovulation and the accomplishment of the pregnancy [63, 65].
3.5 Ovarian cysts
The symptoms of ovarian cysts in cattle typically include: anoestrus is most common, especially during the postpartum period; irregular estrus intervals or regular estrous cycles but lowered fertility; mucometra with normal estrous cycle lengths (if the follicular cysts persist); loss of tone of the female genital tract; behavioral changes (buller cow) which are characteristic of nymphomania (excessive mounting, standing, deeper tone) and erratic milk production. A rise in calving intervals brought on by the existence of such cysts causes the dairy industry to suffer large financial losses [67].
Progesterone concentrations in the peripheral circulation are generally higher in the case of luteal cysts compared to follicular cysts [68]. Limits of P4 concentration for a cyst to be considered luteal should be above 1 ng/mL (plasma) and up to 10 ng/mL (milk). A combination of diagnostic techniques, including transrectal palpation (flaccid uterus in the absence of a corpus luteum, thicker walls than a follicular cyst), transrectal ultrasonography (diameter of the cysts >20 mm), and plasma progesterone profiles, are needed to accurately diagnose the type of ovarian cysts [66, 69, 70].
In buffaloes, when the fluid from the ovarian structures was evaluated, it was observed a higher concentration of P4 in double ovulated (5.5 ng/mL) or normal (5.3 ng/mL) ovaries compared to the ovaries with the follicular cysts (4.7 ng/mL) [71]. However, these results are in contradiction with those of another study [72], in which the progesterone values in the fluid of follicular cysts are higher (49–62 ng/mL) compared to those in the fluid of normal follicles (0.02–27.46 ng/mL).
3.6 Progesterone as an indicator for caseous lymphadenitis
Due to the occurrence of infectious diseases like caseous lymphadenitis in sheep, which is caused by
In a study that compared corpus luteum and progesterone concentrations on days 7 and 20 after mating, the luteal body’s morphology and blood perfusion characteristics did not differ, suggesting that the natural infection caused by
4. Progesterone’s use as a diagnostic tool in horses
4.1 Progesterone in correlation to breeding management
It is widely recognized that the mare is a long-day breeder species; therefore, we expect the reproduction season in the Northern Hemisphere to commence in the spring. So as to determine whether a mare has passed through the reproductive season, serial determination of P4 concentrations in plasma or saliva, which should be below 1 ng/mL, can be utilized [75].
Therefore, it was observed that during the reproductive season, there was a positive correlation (r = 0.68, p < 0.05) between the diameter of the follicles and the levels of P4 recorded from the follicular fluid. However, there was no correlation between the follicle diameter and the levels of P4 assessed from the peripheral venous blood [76].
Recent studies have found evidence suggesting that lower-than-ideal levels of postovulatory P4 may lead to higher rates of embryo death due to decreased endometrial activity in the early stages after ovulation [74, 75]. Therefore, administering progesterone after day 5 post-ovulation would enhance the chances of optimal embryo development [77] and proper chorionic girdle formation in mares [78], especially those that have experienced previous loss of conception product. However, this effect is not observed in young mares [79]. It is worth noting that progesterone receptors are not present in the endometrial epithelium of mares until day 20 post-ovulation [80]. Furthermore, the modification of progestin during the early stages of pregnancy results in enhanced composition of histotrophs in terms of the amino acids lysine and isoleucine [81], leading to a more balanced development of the embryo [78]. However, when there are low levels of P4 at the beginning of the luteal phase, it decreases the negative feedback from the hypothalamic-pituitary axis, which affects the maintenance of pregnancy through secondary luteal structures [82]. Nevertheless, it is important to acknowledge that supplementing with progestins, such as altrenogest, might result in changes to the mare’s immune system and the development of masculine traits in the female fetus [83].
Progesterone is recognized as the hormone that prepares the uterus to receive the embryo and sustain pregnancy [84]. However, it is important to note that during the corpus luteum phase secretion; there is no increase in the blood flow to the endometrium. Therefore, the idea that a larger intake of progesterone in the uterus is not supported [85]. A recent study has found that a progesterone concentration of 6.49 ng/mL, 4 days after ovulation, is required to prime the uterus for receiving the blastocyst and ensuring successful pregnancy in embryo transfer technology [86]. According to the researchers, the vasculature of the corpus luteum, which was measured using Doppler ultrasonography, showed a positive correlation (r = 0.63, p < 0.05) with both the levels of progesterone and the day of embryo transfer [86].
In another study, it was found that mares diagnosed as pregnant at 14 days post-ovulation had a higher P4 level on day 5 post-ovulation (6.4 ± 3.0 ng/mL vs. 5.5 ± 3.3 ng/mL, p = 0.02) than those not diagnosed at the same time [87]. Moreover, double- and triple-gestation mares monitored at the same time interval had significantly higher P4 concentrations than single-gestation mares (9.6 ± 4.9 ng/mL vs. 5.8 ± 2.2 ng/mL, respectively; p = 0.01) [87].
4.2 Disturbed cycles
Despite the fact that the extension of the luteal phase is associated with uterine pathologies, in the case of mares, this phenomenon might occur under circumstances that are not yet fully understood. Approximately 10% of mares can ovulate during diestrus [88]. This phenomenon is characterized by secondary ovulation occurring more than 3 days after the initial ovulation during the follicular phase. If this secondary ovulation occurs beyond the 9th day following the primary ovulation, the luteal phase will be prolonged due to the lack of receptors for prostaglandin F2α in the secondary formed luteal body [89]. Furthermore, the serum concentrations of P4 will be lower than normal levels [88].
4.3 Progesterone-dependent disorders of pregnancy
The maintenance of gestation in mammals is primarily attributed to P4. In mares, gestation is sustained in the initial phase by progesterone secreted by the primary corpus luteum and supplementary corpus luteum (P4 > 4 ng/mL) [90]. However, after day 175 of gestation [91], the level of this hormone drops below 1 ng/mL [84]. When the concentrations of P4 on days 5–7 after ovulation are within the range of >2.5 ng/mL and ≥ 4 ng/mL, they are classified as “suboptimal endogenous P4 concentrations” [87]. After this period, the intricate nature of hormones creates a new challenge in sustaining pregnancy in the mare. Cholesterol from the mother is transported to the fetus and serves as a precursor for pregnenolone (P5) [92]. The enzymes 3β-HSD and 5α-reductase, found in the fetal trophoblast and endometrium, convert P5 into P4 and 5α-dihydroprogesterone (5αDHP) [93]. During the later stages of pregnancy, there is a little rise in the amount of P4 hormone [94]. An immunoenzymatic analysis can indicate potential fetal disorders such as placentitis [95]. Therefore, for acute diseases that resolve within 7 days, P4 concentrations decline quickly. However, for chronic disorders that last for more than 8 days, values tend to increase [96]. Traditionally, the monitoring of these values is done using immunoassay. However, there is a problem with cross-reactivity with other progestins, ranging from 2 to 50%. Therefore, in recent years, liquid chromatography in tandem with mass spectrometry (LC-MS/MS) has been chosen as an alternative. This method can distinguish between P4 and 5αDHP in a single analysis and provide accurate quantitative measurements of these substances. In recent research, the authors found a significant association (r = 0.753, p < 0.001) between low P4 levels (< 6.07 ng/mL) at 14 days of gestation and a high amount of uterine edema during estrus. However, this correlation did not have a detrimental effect on the survivability of the embryos [97, 98].
Furthermore, it is worth noting that primary luteal failure can occur in this species, albeit it is an uncommon occurrence [99]. This phenomenon has been extensively described in the literature, as referenced by sources [94, 95]. Nevertheless, it remains uncertain whether the embryo perishes as a consequence of basic luteal failure or due to the inability of the mother to recognize the pregnancy [100]. In one of the mentioned cases, the levels of exogenous P4 were below 2 ng/mL from days 15 to 72. However, the pregnancy was successfully carried out after the administration of progestogen [100].
4.4 Postpartum progesterone-dependent disorders
Another research found that progesterone receptors in the endometrial glands and stroma of mares are more intense and frequent during the luteal phase compared to the follicular phase. However, no association with the endometritis was discovered [101]. This finding contradicts the outcomes of another group of researchers who reported that endometrial fibrosis significantly reduces the expression of P4 and estradiol receptors [102].
5. Progesterone’s use as a diagnostic tool in pigs
5.1 Specific progesterone characteristics throughout the estrus cycle and gestation
When monitoring progesterone levels in sows, it is important to consider that the levels of P4 in blood drawn from the caudal vena cava are greater than those collected from the jugular vein [103]. Furthermore, the concentration of P4 is greater in the oviductal region compared to the bloodstream, indicating the undisputed function of this hormone in the release of spermatozoa from the oviductal region [104].
One specific characteristic of pig reproduction that is similar to the wild boar is the seasonal subfertility that happens between August and October in the Northern Hemisphere as a result of heat stress [102, 103]. Therefore, this subfertility leads to the production of small litter size, higher rates of abortion, delayed onset of sexual maturity, decreased rates of successful conception, and a longer interval between weaning to estrous [105]. New research on post-pubertal gilts revealed that higher temperature stress results in the development of smaller luteal bodies. However, these smaller luteal bodies have the ability to produce a greater amount of P4 per unit of luteal tissue [106]. Nevertheless, it is important to consider the influence of nutrition on the secretion of P4 and the subsequent survival of the embryo, particularly in the initial days after ovulation [107]. This effect is likely related to the regulation of the orexin system by P4 [108]. Therefore, subjecting pregnant sows to a period of 45 days of starvation during the first trimester of gestation led to 25% of the sows maintaining their pregnancy [109].
The proper operation of the corpus luteum requires a substantial and crucial intake of lipid-rich substances and IGF-1, which are essential for the production of P4. During the initial stages of pregnancy, namely after ovulation, the ovaries produce less progesterone (2 ng/mL after 6 hours) [104] because to its breakdown in the liver. Following that, there is a rapid surge in the period from day 10 to day 13 of gestation [107]. To further corroborate the statement, the following values serve as indicators:
During the estrous cycle, the levels of a certain hormone called ng/mL fluctuate. On days 2–4, the average level is 7.2 ± 0.97 ng/mL. On days 10–12, the average level increases to 16.44 ± 2.18 ng/mL. On days 14–16, the average level drops to 1.03 ± 0.19 ng/mL. Finally, on days 18–20, the average level further decreases to 0.91 ± 0.18 ng/mL [109].
During gestation, the levels of ng/mL also vary. On days 14–16, the average level is 21.24 ± 3.05 ng/mL. On days 30–32, the average level increases to 23.45 ± 3.39 ng/mL [110]. From days 30 to 105, the average level remains relatively stable, ranging from 18 to 25 ng/mL [109].
5.2 Lactation through the lens of progesterone
Effective control of parturition is crucial for the future well-being of newborn piglets. Specifically, in the case of pigs, pregnant females exhibit nest-building behavior when there is a fall in P4 levels and an increase in prolactin values before farrowing [111]. Furthermore, when females have a lack of or restricted access to various resources for constructing their nest, they will exhibit elevated P4 levels [112].
Recent research has found that there are positive connections between the quality or amount of colostrum and other factors influenced by the sow, which can ultimately result in the death of newborn piglets. Based on research, P4 levels were deemed to exceed the limitations at the beginning of farrowing when they were greater than 6 ng/mL and greater than 4.9 ng/mL at the end of the farrowing [113]. The authors found that 50% of the subjects had abnormal P4 values at both time points mentioned. They concluded that piglets born to sows with P4 values greater than 4.9 ng/mL at the end of parturition were more likely to develop neonatal diarrhea on the first day of life. The odds ratio was 3.71, with a confidence interval of 1.04–13.23 and a p-value of 0.04. This increased risk was attributed to low immunological levels.
Furthermore, elevated levels of progesterone during the initial 48 hours after farrowing might result in the birth of underdeveloped piglets, disrupt milk production and indicate that those sows had a big litter [114]. Contrarily, a little amount of P4 before farrowing results in an increase in the production of colostrum without any impact on its quality [115].
6. Conclusion
This chapter describes in as practical a way as possible the need to assess progesterone levels, often in combination with other hormones or medical procedures. Given the myriad practical applications in which it can be used, it is not wrong to use the term as a marker for certain physiological, but especially pathological, conditions. This capital is far from being considered complete, but we hope it will be exploited to the fullest until new studies improve the present work.
Acknowledgments
We are grateful to our colleagues and students from the Faculty of Veterinary Medicine at the University of Agronomical Sciences and Veterinary Medicine of Bucharest. We owe them who we are now as professionals.
References
- 1.
Fontbonne A, Maenhoudt C, Thoumire S, et al. Evaluation of surface plasmon field-enhanced fluorescence spectroscopy for rapid measurement of progesterone concentration in bitches. American Journal of Veterinary Research. 2021; 82 (5):417-424. DOI: 10.2460/ajvr.82.5.417 - 2.
De Cramer KGM, Nöthling JO. The precision of predicting the time of onset of parturition in the bitch using the level of progesterone in plasma during the preparturient period. Theriogenology. 2018; 107 :211-218. DOI: 10.1016/j.theriogenology.2017.11.018 - 3.
de Gier J, Kooistra HS, Djajadiningrat-Laanen SC, Dieleman SJ, Okkens AC. Temporal relations between plasma concentrations of luteinizing hormone, follicle-stimulating hormone, estradiol-17β, progesterone, prolactin, and α-melanocyte-stimulating hormone during the follicular, ovulatory, and early luteal phase in the bitch. Theriogenology. 2006; 65 (7):1346-1359. DOI: 10.1016/j.theriogenology.2005.08.010 - 4.
González SL, Labombarda F, Deniselle MCG, Guennoun R, Schumacher M, De Nicola AF. Progesterone up-regulates neuronal brain-derived neurotrophic factor expression in the injured spinal cord. Neuroscience. 2004; 125 (3):605-614. DOI: 10.1016/j.neuroscience.2004.02.024 - 5.
Yarim GF, Karahan S, Yarim M. Cerebellum progesterone concentration decreased in canine distemper virus infection. Research in Veterinary Science. 2007; 82 (2):173-180. DOI: 10.1016/j.rvsc.2006.05.008 - 6.
Lerouet D, Marchand-Leroux C, Besson VC. Neuropharmacology in traumatic brain injury: From preclinical to clinical neuroprotection? Fundamental & Clinical Pharmacology. 2021; 35 (3):524-538. DOI: 10.1111/fcp.12656 - 7.
Behrend EN, Kooistra HS, Nelson R, Reusch CE, Scott-Moncrieff JC. Diagnosis of spontaneous canine Hyperadrenocorticism: 2012 ACVIM consensus statement (small animal). Journal of Veterinary Internal Medicine. 2013; 27 (6):1292-1304. DOI: 10.1111/jvim.12192 - 8.
Farges A, Crawford D, da Silva CA, Ramsey I. Hyperprogesteronism associated with adrenocortical tumours in two dogs. Veterinary Record Case Reports. 2024; 12 (e794):1-9. DOI: 10.1002/vrc2.794 - 9.
Pöppl ÁG, Lopes JLX, Nogueira TB, da Silva DI, dos Santos MB. Progesterone-related diabetes mellitus in the bitch: Current knowledge, the role of Pyometra, and relevance in practice. Animals. 2024; 14 (6):890. DOI: 10.3390/ani14060890 - 10.
Hollinshead F, Hanlon D. Normal progesterone profiles during estrus in the bitch: A prospective analysis of 1420 estrous cycles. Theriogenology. 2019; 125 :37-42. DOI: 10.1016/j.theriogenology.2018.10.018 - 11.
Risvanli A, Ocal H, Kalkan C. Abnormalities in the sexual cycle of bitches. In: Canine Medicine - Recent Topics and Advanced Research. London, UK, London, UK: InTech; 2016. DOI: 10.5772/64648 - 12.
Guérin C, Maurel MC, Launais M, Delétang F, Badinand F. Use of an immunoenzymatic assay to detect the luteinizing hormone peak in bitches. Journal of Reproduction and Fertility. Supplement. 1997; 51 :277-281 - 13.
Concannon PW. Reproductive cycles of the domestic bitch. Animal Reproduction Science. 2011; 124 (3-4):200-210. DOI: 10.1016/j.anireprosci.2010.08.028 - 14.
Jensen SØ, Öberg J, Alm H, Holst BS. Validation of a dry-slide immunoassay for progesterone analysis in canine plasma in a clinical setting. Veterinary Clinical Pathology. 2022; 51 (4):524-532. DOI: 10.1111/vcp.13140 - 15.
Kunanusont N, Punyadarsaniya D, Ruenphet S. Accuracy and precision guidelines for optimal breeding time in bitches using in-house progesterone measurement compared with chemiluminescent microparticle immunoassay. Veterinary World. 2021; 14 (3):585-588. DOI: 10.14202/vetworld.2021.585-588 - 16.
Zuercher J, Boes KM, Balogh O, Helms AB, Cecere JT. Comparison of a point-of-care Analyzer with a Chemiluminescent immunoassay for serum progesterone measurement in breeding Management of the Bitch. Frontiers in Veterinary Science. 2021; 8 :1-9. DOI: 10.3389/fvets.2021.660923 - 17.
Kustritz MVR. Managing the reproductive cycle in the bitch. The Veterinary Clinics of North America. Small Animal Practice. 2012; 42 (3):423-437. DOI: 10.1016/j.cvsm.2012.01.012 - 18.
Groppetti D, Aralla M, Bronzo V, Bosi G, Pecile A, Arrighi S. Periovulatory time in the bitch: What’s new to know? Animal Reproduction Science. 2015; 152 :108-116. DOI: 10.1016/j.anireprosci.2014.11.008 - 19.
Milani C, Boscato EL, Gabai G, et al. Analytical and clinical performance of a fluorescence enzyme immunoassay for progesterone and determination of ovulation day in bitches. Journal of Veterinary Diagnostic Investigation. 2022; 34 (6):977-982. DOI: 10.1177/10406387221125466 - 20.
Johnston SD. Clinical approach to infertility in bitches with primary Anestrus. The Veterinary Clinics of North America. Small Animal Practice. 1991; 21 (3):421-425. DOI: 10.1016/S0195-5616(91)50051-6 - 21.
Johnson AK. Breeding and cattery management. In: Feline Reproduction. Boston: CABI; 2022. pp. 41-46. DOI: 10.1079/9781789247107.0004 - 22.
Goericke-Pesch S, Packeiser E-M. Reproductive Management in Catteries: Optimising health and wellbeing through veterinarian-breeder collaboration. Journal of Feline Medicine and Surgery. 2022; 24 (9):881-904. DOI: 10.1177/1098612X221118760 - 23.
Gobello C, Castex G, Corrada Y. Use of cabergoline to treat primary and secondary anestrus in dogs. Journal of the American Veterinary Medical Association. 2002; 220 (11):1653-1654. DOI: 10.2460/javma.2002.220.1653 - 24.
Johnston SD, Root Kustritz MV, Schultz OP. In: Company WS, editor. Canine and Feline Theriogenology. 1st ed. Philadelphia: Saunders; 2001 - 25.
Wilborn RR, Maxwell HS. Clinical approaches to infertility in the bitch. The Veterinary Clinics of North America. Small Animal Practice. 2012; 42 (3):457-468. DOI: 10.1016/j.cvsm.2012.01.016 - 26.
Meyers-Wallen VN. Unusual and abnormal canine estrous cycles. Theriogenology. 2007; 68 (9):1205-1210. DOI: 10.1016/j.theriogenology.2007.08.019 - 27.
Arbeiter K. Anovulatory ovarian cycles in dogs. Journal of Reproduction and Fertility. Supplement. 1993; 47 :453-456 - 28.
Fontbonne A, Niewiadomska Z. Causes of infertility in the queen. In: Feline Reproduction. Boston: CABI; 2022. pp. 47-55. DOI: 10.1079/9781789247107.0005 - 29.
Place NJ, Cheraskin J-L, Hansen BS. Evaluation of combined assessments of serum anti-Müllerian hormone and progesterone concentrations for the diagnosis of ovarian remnant syndrome in dogs. Journal of the American Veterinary Medical Association. 2019; 254 (9):1067-1072. DOI: 10.2460/javma.254.9.1067 - 30.
Axnér E, Holst BS. Concentrations of anti-Müllerian hormone in the domestic cat. Relation with spay or neuter status and serum estradiol. Theriogenology. 2015; 83 (5):817-821. DOI: 10.1016/j.theriogenology.2014.11.016 - 31.
Mullikin K, Byron M, Chen J, Cheong SH, Gartley C, de Amorim MD. Ovarian remnant syndrome in small animals: Case series. Clinical Theriogenology. 2022; 14 (4):370-377. DOI: 10.58292/ct.v14i4.9174 - 32.
Pires MA, Payan-Carreira R. Cystic structures in the canine ovary: A prevalence survey. In: EVSSAR, editor. 17th EVSSAR Conference-Reproduction and Pediatrics in Dogs, Cats and Exotic Carnivores. Wroclaw: EVSSAR; 2017. p. 179 - 33.
Fontbonne A. Infertility in bitches and queens: recent advances Infertilidade na cadela e gata: atualidades. Revista Brasileira de Reprodução Animal. 2011; 35 (2):202-209. Available from:www.cbra.org.br - 34.
Knauf Y, Bostedt H, Failing K, Knauf S, Wehrend A. Gross pathology and endocrinology of ovarian cysts in bitches. Reproduction in Domestic Animals. 2014; 49 (3):463-468. DOI: 10.1111/rda.12311 - 35.
Ehrhardt C, Odunayo A, Pascutti K, Carvajal J, Ham K, Harris AN. Stump pyometra in a spayed female dog secondary to tamoxifen. Veterinary Medicine and Science. 2023; 9 (1):47-52. DOI: 10.1002/vms3.1041 - 36.
Xavier RGC, Santana CH, de Castro YG, et al. Canine Pyometra: A short review of current advances. Animals. 2023; 13 (21):3310. DOI: 10.3390/ani13213310 - 37.
Johnson A. Diagnosis and medical treatment of pyometra in the queen. Clinical Theriogenology. 2022; 14 (3):151-154. DOI: 10.58292/ct.v14i3.9165 - 38.
Holst BS. Feline breeding and pregnancy management: What is normal and when to intervene. Journal of Feline Medicine and Surgery. 2022; 24 (3):221-231. DOI: 10.1177/1098612X221079708 - 39.
Roos J, Fontbonne A. Pregnancy diagnosis and management. In: Feline Reproduction. Boston: CABI; 2022. pp. 56-73. DOI: 10.1079/9781789247107.0006 - 40.
Levy X, England GCW. Pregnancy diagnosis, normal pregnancy and parturition in the queen. In: BSAVA Manual of Canine and Feline Reproduction and Neonatology. London: British Small Animal Veterinary Association; 2010. pp. 98-105. DOI: 10.22233/9781905319541.11 - 41.
Graham EM, Taylor DJ. Bacterial reproductive pathogens of cats and dogs. The Veterinary Clinics of North America. Small Animal Practice. 2012; 42 (3):561-582. DOI: 10.1016/j.cvsm.2012.01.013 - 42.
Verstegen J, Dhaliwal G, Verstegen-Onclin K. Canine and feline pregnancy loss due to viral and non-infectious causes: A review. Theriogenology. 2008; 70 (3):304-319. DOI: 10.1016/j.theriogenology.2008.05.035 - 43.
Root Kustritz MV. Use of supplemental progesterone in Management of Canine Pregnancy. In: Concannon PW, England G, Verstegen J III, Linde Forsberg C, editors. Recent Advances in Small Animal Reproduction. Ithaca: International Veterinary Information Service; 2001 - 44.
Becher A, Wehrend A, Goericke-Pesch S. Luteale Insuffizienz bei der Hündin – Symptome, Diagnose, Folgen und Therapie. Tierärztliche Prax Ausgabe K Kleintiere/Heimtiere. 2010; 38 (06):389-396. DOI: 10.1055/s-0038-1622870 - 45.
Dolf G, Gaillard C, Russenberger J, Moseley L, Schelling C. Factors contributing to the decision to perform a cesarean section in Labrador retrievers. BMC Veterinary Research. 2018; 14 (1):1-9. DOI: 10.1186/s12917-018-1381-8 - 46.
Smith FO. Challenges in small animal parturition—Timing elective and emergency cesarian sections. Theriogenology. 2007; 68 (3):348-353. DOI: 10.1016/j.theriogenology.2007.04.041 - 47.
Nöthling JO, Joonè CJ, Hegarty E, Schooley EK, De Cramer KGM. Use of a point-of-care progesterone assay to predict onset of parturition in the bitch. Frontiers in Veterinary Science. 2022; 9 :1-6. DOI: 10.3389/fvets.2022.914659 - 48.
De Cramer KGM, Nöthling JO. Towards scheduled pre-parturient caesarean sections in bitches. Reproduction in Domestic Animals. 2020; 55 (S2):38-48. DOI: 10.1111/rda.13669 - 49.
Eigenmann JE, Eigenmann RY, Rijnberk A, van der Gaag I, Zapf J, Froesch ER. Progesterone-controlled growth hormone overproduction and naturally occurring canine diabetes and acromegaly. Acta Endocrinologica. 1983; 104 (2):167-176. DOI: 10.1530/acta.0.1040167 - 50.
Syme HM, Scott-Moncrieff JC, Treadwell NG, et al. Hyperadr-enocorticism associated with excessive sex hormone production by an adrenocortical tumor in two dogs. Journal of the American Veterinary Medical Association. 2001; 219 (12):1725-1728. DOI: 10.2460/javma.2001.219.1725 - 51.
Schumacher M, Guennoun R, Robert F, et al. Local synthesis and dual actions of progesterone in the nervous system: Neuroprotection and myelination. Growth Hormone & IGF Research. 2004; 14 :18-33. DOI: 10.1016/j.ghir.2004.03.007 - 52.
Roelofs JB, Van Eerdenburg FJCM, Hazeleger W, Soede NM, Kemp B. Relationship between progesterone concentrations in milk and blood and time of ovulation in dairy cattle. Animal Reproduction Science. 2006; 91 (3-4):337-343. DOI: 10.1016/j.anireprosci.2005.04.015 - 53.
Bruinjé TC, Colazo MG, Ribeiro ES, Gobikrushanth M, Ambrose DJ. Using in-line milk progesterone data to characterize parameters of luteal activity and their association with fertility in Holstein cows. Journal of Dairy Science. 2019; 102 (1):780-798. DOI: 10.3168/jds.2018-14654 - 54.
Hirata S, Mori Y. Monitoring reproductive status by Fecal progesterone analysis in ruminants. The Journal of Veterinary Medical Science. 1995; 57 (5):845-850. DOI: 10.1292/jvms.57.845 - 55.
Jack AMM, Chang CC, Peh HC, Chan JPW. Fecal progesterone analysis for monitoring reproductive status in dairy goats. Turkish Journal of Veterinary & Animal Sciences. 2012; 36 (5):566-572. DOI: 10.3906/vet-1105-1 - 56.
Osman K, El-Regalaty H, Fekry A, Farghaly H, Aboul-Ela H. Use of milk progesterone assay for monitoring ovulation, ovarian cycles and pregnancy in buffalo. Journal of Animal and Poultry Production. 2010; 1 (5):163-174. DOI: 10.21608/jappmu.2010.86199 - 57.
Gábor G, Kastelic J, Abonyi-Tóth Z, Gábor P, Endrődi T, Balogh O. Pregnancy loss in dairy cattle: Relationship of ultrasound, blood pregnancy-specific protein B, progesterone and production variables. Reproduction in Domestic Animals. 2016; 51 (4):467-473. DOI: 10.1111/rda.12703 - 58.
Bekele N, Addis M, Abdela N, Ahmed WM. Pregnancy diagnosis in cattle for fertility management: A review. Global Veterinary. 2016; 16 (4):355-364. DOI: 10.5829/idosi.gv.2016.16.04.103136 - 59.
Isobe N, Akita M, Nakao T, Yamashiro H, Kubota H. Pregnancy diagnosis based on the fecal progesterone concentration in beef and dairy heifers and beef cows. Animal Reproduction Science. 2005; 90 (3-4):211-218. DOI: 10.1016/j.anireprosci.2005.02.004 - 60.
Constantin NT, Bercea-Strugariu CM, Bîrțoiu D, et al. Predicting pregnancy outcome in dairy cows: The role of IGF-1 and progesterone. Animals. 2023; 13 (10):1579. DOI: 10.3390/ani13101579 - 61.
Codreanu I, Codreanu M. Study regarding hormonal and biochemical profiles in pregnant and lactating ewes treated with bromocriptine. Scientific Works C Series; LVII(3):54-57 - 62.
Ganaie BA, Khan MZ, Islam R, Makhdoomi DM, Qureshi S, Wani GM. Evaluation of different techniques for pregnancy diagnosis in sheep. Small Ruminant Research. 2009; 85 (2-3):135-141. DOI: 10.1016/j.smallrumres.2009.09.003 - 63.
Codognoto VM, Souza FF, Salgado LC, et al. Can blood progesterone concentration identify non-pregnant buffaloes to support oestrous resynchronization. Reproduction in Domestic Animals. 2022; 57 (6):673-677 - 64.
Kornmatitsuk B, Chantaraprateep P, Kornmatitsuk S, Kindahl H. Different types of postpartum luteal activity affected by the exposure of heat stress and subsequent reproductive performance in Holstein lactating cows. Reproduction in Domestic Animals. 2008; 43 (5):515-519. DOI: 10.1111/j.1439-0531.2007.00945.x - 65.
López-Gatius F, Garcia-Ispierto I. Clinical overview of luteal deficiency in dairy cattle. Animals. 2022; 12 (15):1-7. DOI: 10.3390/ani12151871 - 66.
Beindorff N, Nagai K, Shirasuna K, et al. Vascular changes in the corpus luteum during early pregnancy in the cow. The Journal of Reproduction and Development. 2010; 56 (2):263-270. DOI: 10.1262/jrd.09-150K - 67.
Jeengar K, Chaudhary V, Kumar A, Raiya S, Gaur M, Purohit GN. Ovarian cysts in dairy cows: Old and new concepts for definition. Diagnosis and Therapy. 2014; 11 (2):63-73 - 68.
Ochea M, Pascal M, Şonea A, Bîrţoiu AI. The effect of epidural administration of FSH in bovine superovulation protocol. Animal Science. 2015; 58 :217-220 - 69.
Spencer TE, Forde N, Lonergan P. The role of progesterone and conceptus-derived factors in uterine biology during early pregnancy in ruminants1. Journal of Dairy Science. 2016; 99 (7):5941-5950. DOI: 10.3168/jds.2015-10070 - 70.
Turner ZB, Lima FS, Conley AJ, et al. Cystic ovarian disease in dairy cattle: Diagnostic accuracy when using B-mode and color Doppler ultrasound. Journal of Dairy Science. 2023; 106 (5):3411-3420. DOI: 10.3168/jds.2022-22498 - 71.
Zeitoun MM. Effect of physiological status of buffalo ovaries on progesterone and biochemical constituents in follicular fluids. In: Proceedings of the 26th Annual Meeting of the Brazilian Embryo Technology Society (SBTE). Alexandria: SBTE; 2012 - 72.
Khan FA, Nabi SU, Pande M, Das GK, Sarkar M. Bilateral follicular cysts in a water buffalo. Tropical Animal Health and Production. 2011; 43 (3):539-541. DOI: 10.1007/s11250-010-9738-4 - 73.
Pépin M, Paton MW. Caseous lymphadenitis in sheep and goats. In: Lefevre PC, Blancou J, Chermette R, Uilenberg G, editors. Infectious and Parasitic Disease of Livestock. 1st ed. Paris: Lavoisier; 2010. 1153 p - 74.
Costa JO, Barral TD, Portela RD, et al. Correlation between the natural infection by Corynebacterium pseudotuberculosis in goats and serum progesterone levels and corpus luteum development. Domestic Animal Endocrinology. 2022; 78 :106677. DOI: 10.1016/j.domaniend.2021.106677 - 75.
Goudet G, Douet C, Pianos A, et al. Saliva and plasma steroidome in mare during reproductive stages: A GC-MS/MS study. Frontiers in Animal Science. 2022; 3 (October):1-18. DOI: 10.3389/fanim.2022.1055179 - 76.
Satué K, Fazio E, Ferlazzo A, Medica P. Intrafollicular and systemic serotonin, oestradiol and progesterone concentrations in cycling mares. Reproduction in Domestic Animals. 2019; 54 (10):1411-1418. DOI: 10.1111/rda.13545 - 77.
Willmann C, Budik S, Walter I, Aurich C. Influences of treatment of early pregnant mares with the progestin altrenogest on embryonic development and gene expression in the endometrium and conceptus. Theriogenology. 2011; 76 (1):61-73. DOI: 10.1016/j.theriogenology.2011.01.018 - 78.
Okada CTC, Kaps M, Reichart U, et al. Low plasma progesterone concentration during the early luteal phase delays endometrial development and the beginning of placentation in mares. Animal Reproduction Science. 2022; 247 :1-12. DOI: 10.1016/j.anireprosci.2022.107149 - 79.
Willmann C, Schuler G, Hoffmann B, Parvizi N, Aurich C. Effects of age and altrenogest treatment on conceptus development and secretion of LH, progesterone and eCG in early-pregnant mares. Theriogenology. 2011; 75 (3):421-428. DOI: 10.1016/j.theriogenology.2010.05.009 - 80.
Wilsher S, Gower S, Allen WRT. Immunohistochemical localisation of progesterone and oestrogen receptors at the placental interface in mares during early pregnancy. Animal Reproduction Science. 2011; 129 (3-4):200-208. DOI: 10.1016/j.anireprosci.2011.11.004 - 81.
Beyer T, Rink BE, Scarlet D, Walter I, Kunert S, Aurich C. Early luteal phase progestin concentration influences endometrial function in pregnant mares. Theriogenology. 2019; 125 :236-241. DOI: 10.1016/j.theriogenology.2018.11.018 - 82.
Okada CTC, Kaps M, Quesada JP, Gautier C, Aurich J, Aurich C. Diestrous ovulations in pregnant mares as a response to low early postovulatory progestogen concentration. Animals. 2020; 10 (12):1-9. DOI: 10.3390/ani10122249 - 83.
Fedorka CE, Troedsson MHT. The use of progestins in equine medicine: A review. Equine Veterinary Education. 2021; 33 (9):494-504. DOI: 10.1111/eve.13332 - 84.
Wynn MAA, Esteller-Vico A, Legacki EL, et al. A comparison of progesterone assays for determination of peripheral pregnane concentrations in the late pregnant mare. Theriogenology. 2018; 106 :127-133. DOI: 10.1016/j.theriogenology.2017.10.002 - 85.
Ginther OJ, Beg MA. Dynamics of circulating progesterone concentrations before and during luteolysis: A comparison between cattle and horses. Biology of Reproduction. 2012; 86 (6):1-12. DOI: 10.1095/biolreprod.112.099820 - 86.
Sales FABM, Vasconcelos Azevedo M, Matos Souza N, et al. Correlations of corpus luteum blood flow with fertility and progesterone in embryo recipient mares. Tropical Animal Health and Production. 22 Apr 2021; 53 (2):280. DOI: 10.1007/s11250-021-02583-9 - 87.
Hollinshead FK, Mehegan MK, Gunn A, Nett T, Bruemmer JE, Hanlon DW. The correlation of endogenous progesterone concentration in Diestrus on early pregnancy rate in thoroughbred mares. Journal of Equine Veterinary Science. 2022; 118 :104127. DOI: 10.1016/j.jevs.2022.104127 - 88.
Von Hippel FA. The reproductive cycle. Tinbergen’s Leg Behav Sixty Years Landmark Stickleback Paper. 2010; 8 (December):23-39. DOI: 10.1163/ej.9789004170292.i-540.7 - 89.
Ginther OJ. Prolonged luteal activity in mares - a semantic quagmire. Equine Veterinary Journal. 1990; 22 (3):152-156. DOI: 10.1111/j.2042-3306.1990.tb04235.x - 90.
Shideler RK, Squires EL, Voss JL, Eikenberry DJ, Pickett BW. Progestagen therapy of ovariectomized pregnant mares. Journal of Reproduction and Fertility. 1982; 32 (459-464):16 - 91.
Popova M. Breeding age of mares from the Haflinger breed, duration of gestational length and the influence of some Paratype factors on it. Scientific Papers. Series D. Animal Science. 2020; LXIII (1):263-270 - 92.
Chavatte P, Holtan D, Ousey JC, Rossdale PD. Biosynthesis and possible biological roles of progestagens during equine pregnancy and in the newborn foal. Equine Veterinary Journal. Supplement. 1997; 24 (24):89-95. DOI: 10.1111/j.2042-3306.1997.tb05084.x - 93.
Han X, Rossdale PD, Ousey J, et al. Localisation of 15-hydroxy prostaglandin dehydrogenase (PGDH) and steroidogenic enzymes in the equine placenta. Equine Veterinary Journal. 1995; 27 (5):334-339. DOI: 10.1111/j.2042-3306.1995.tb04067.x - 94.
Conley AJ. Review of the reproductive endocrinology of the pregnant and parturient mare. Theriogenology. 2016; 86 (1):355-365. DOI: 10.1016/j.theriogenology.2016.04.049 - 95.
Ousey JC, Houghton E, Grainger L, Rossdale PD, Fowden AL. Progestagen profiles during the last trimester of gestation in thoroughbred mares with normal or compromised pregnancies. Theriogenology. 2005; 63 (7):1844-1856. DOI: 10.1016/j.theriogenology.2004.08.010 - 96.
Morris S, Kelleman AA, |Stawicki RJ, et al. Transrectal ultrasonography and plasma progestin profiles identifies feto-placental compromise in mares with experimentally induced placentitis. Theriogenology. 2007; 67 (4):681-691. DOI: 10.1016/j.theriogenology.2006.05.021 - 97.
Grabowska A, Kozdrowski R. Relationship between estrus endometrial edema and progesterone production in pregnant mares two weeks after ovulation. BMC Veterinary Research. 2022; 18 (1):1-8. DOI: 10.1186/s12917-022-03512-0 - 98.
Allen WR. Luteal deficiency and embryo mortality in the mare. Reproduction in Domestic Animals. 2001; 36 (3-4):121-131. DOI: 10.1046/j.1439-0531.2001.d01-43.x - 99.
Vanderwall DK, Squires EL, Brinsko SP, McCue PM. Diagnosis and management of abnormal embryonic development characterized by formation of an embryonic vesicle without an embryo in mares. Journal of the American Veterinary Medical Association. 2000; 217 (1):58-63. DOI: 10.2460/javma.2000.217.58 - 100.
Canisso IF, Beltaire KA, Bedford-Guaus SJ. Premature luteal regression in a pregnant mare and subsequent pregnancy maintenance with the use of oral altrenogest. Equine Veterinary Journal. 2013; 45 (1):97-100. DOI: 10.1111/j.2042-3306.2012.00559.x - 101.
Rojas D, Cabezas J, Ramírez G, Saravia F, Rodriguez-Alvarez L, Castro FO. Complimentary diagnostic tools for endometrosis in biopsies of mares with clinical subfertility. Acta Scientiae Veterinariae. 2020; 48 (1):1-9. DOI: 10.22456/1679-9216.98312 - 102.
Hoffmann C, Bazer FW, Klug J, Aupperle H, Ellenberger C, Schoon HA. Immunohistochemical and histochemical identification of proteins and carbohydrates in the equine endometrium. Expression patterns for mares suffering from endometrosis. Theriogenology. 2009; 71 (2):264-274. DOI: 10.1016/j.theriogenology.2008.07.008 - 103.
Virolainen JV, Love RJ, Tast A, Peltoniemi OAT. Plasma progesterone concentration depends on sampling site in pigs. Animal Reproduction Science. 2005; 86 (3-4):305-316. DOI: 10.1016/j.anireprosci.2004.07.004 - 104.
Mirihagalle S, Hughes JR, Miller DJ. Progesterone-induced sperm release from the oviduct sperm reservoir. Cells. 2022; 11 (10):1-13. DOI: 10.3390/cells11101622 - 105.
Bertoldo M, Holyoake PK, Evans G, Grupen CG. Follicular progesterone levels decrease during the period of seasonal infertility in sows. Reproduction in Domestic Animals. 2011; 46 (3):489-494. DOI: 10.1111/j.1439-0531.2010.01695.x - 106.
Bidne KL, Romoser MR, Ross JW, Baumgard LH, Keating AF. Heat stress during the luteal phase decreases luteal size but does not affect circulating progesterone in gilts. Journal of Animal Science. 2019; 97 (10):4314-4322. DOI: 10.1093/jas/skz251 - 107.
Langendijk P, Peltoniemi O. How does nutrition influence luteal function and early embryo survival. Bioscientifica Proceedings. 2019; 1 :145-158. DOI: 10.1530/biosciprocs.19.0015 - 108.
Dobrzyn K, Smolinska N, Kiezun M, et al. The in vitro effect of progesterone on the orexin system in porcine uterine tissues during early pregnancy. Acta Veterinaria Scandinavica. 2018; 60 (1):1-14. DOI: 10.1186/s13028-018-0430-4 - 109.
Hard DL, Anderson LL. Maternal starvation and progesterone secretion, litter size, and growth in the pig. American Journal of Physiology-Endocrinology and Metabolism Gastrointestinal Physiology. 1979; 6 (3):273-278. DOI: 10.1152/ajpendo.1979.237.3.e273 - 110.
Skowronska A, Mlotkowska P, Eliszewski M, Nielsen S, Skowronski MT. Expression of aquaporin 1, 5 and 9 in the ovarian follicles of cycling and early pregnant pigs. Physiological Research. 2015; 64 (2):237-245. DOI: 10.33549/physiolres.932825 - 111.
Yun J, Swan KM, Farmer C, Oliviero C, Peltoniemi O, Valros A. Prepartum nest-building has an impact on postpartum nursing performance and maternal behaviour in early lactating sows. Applied Animal Behaviour Science. 2014; 160 (1):31-37. DOI: 10.1016/j.applanim.2014.08.011 - 112.
Yun J, Swan KM, Vienola K, et al. Nest-building in sows: Effects of farrowing housing on hormonal modulation of maternal characteristics. Applied Animal Behaviour Science. 2013; 148 (1-2):77-84. DOI: 10.1016/j.applanim.2013.07.010 - 113.
Hasan SMK, Junnikkala S, Valros A, Peltoniemi O, Oliviero C. Validation of brix refractometer to estimate colostrum immunoglobulin G content and composition in the sow. Animal. 2016; 10 (10):1728-1733. DOI: 10.1017/S1751731116000896 - 114.
De Passille AMB, Rushen J, Foxcroft GR, Schaefers A. Performance of Young Pigs: Relationships with Periparturient Progesterone, Prolactin, and Insulin of Sows’. Available from: https://academic.oup.com/jas/article-abstract/71/1/179/4632101 - 115.
Loisel F, Farmer C, van Hees H, Quesnel H. Relative prolactin-to-progesterone concentrations around farrowing influence colostrum yield in primiparous sows. Domestic Animal Endocrinology. 2015; 53 :35-41. DOI: 10.1016/j.domaniend.2015.04.005