Medroxyprogesterone Acetate Reduced Cellular Proliferation of the Luminal and Glandular Epithelium in the Developing Canine Uterus (original) (raw)
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Postnatal exposure to a progestin does not prevent uterine adenogenesis in domestic dogs
Journal of veterinary science, 2015
To assess the effect of a single supraphysiological postnatal administration of a progestagen on uterine glands in dogs, 10 females were randomly assigned to: Medroxyprogesterone acetate 35 mg (MPA; n=6) or Placebo (n = 4) within the first 24 h of birth. The safety of the treatment was also evaluated. A transient mild clitoris enlargement appeared in MPA-treated females. Microscopic postpubertal uterine assessment revealed the presence of uterine glands in all the cases without significant differences in the area occupied by the glands per µm(2) of endometrium nor in the height of the uterine epithelium.
Animal Reproduction
Bitches with uteri devoid of endometrial glands should be sterile, and consequently could contribute to the population control of dogs. Considering that an inadequate exposure of the female reproductive system to steroids can lead to the formation of the uterine gland knockout (UGKO) phenotype in some species, the aim of this study was to evaluate the effect of serial applications of medroxyprogesterone acetate (MPA) from birth until the age of six months on the development of endometrial glands in bitches. For this purpose, 16 female mongrel dogs from different litters were distributed into either an MPA group (n = 8), animals treated with 10 mg kg sc (Promone-E ® , Pfizer, Brasil) at 3-week intervals, from day one after birth until the age of six months, or a control group (n = 8), composed of animals that only received a 0.9% NaCl solution in place of MPA. At six months of age, ovariohysterectomy was performed and uterine horn samples were collected for histological and immunohistochemical examinations. The bitches from the MPA-treated group presented a 35% decrease in the number of endometrial glands, a larger diameter of the endometrial glands, a greater epithelial height, as well as a greater thickness of the uterine wall, endometrium, and myometrium. However, no significant differences were observed between the two groups in the expression of ER-α, ER-β, and PR on the surface epithelium and endometrial stroma. Therefore, the serial application of MPA from birth until the age of 6 months do not completely ablate the development of the endometrial glands in bitches, but impair it by 35%.
Uterine glands: development, function and experimental model systems
Molecular Human Reproduction, 2013
Development of uterine glands (adenogenesis) in mammals typically begins during the early post-natal period and involves budding of nascent glands from the luminal epithelium and extensive cell proliferation in these structures as they grow into the surrounding stroma, elongate and mature. Uterine glands are essential for pregnancy, as demonstrated by the infertility that results from inhibiting the development of these glands through gene mutation or epigenetic strategies. Several genes, including forkhead box A2, beta-catenin and members of the Wnt and Hox gene families, are implicated in uterine gland development. Progestins inhibit uterine epithelial proliferation, and this has been employed as a strategy to develop a model in which progestin treatment of ewes for 8 weeks from birth produces infertile adults lacking uterine glands. More recently, mouse models have been developed in which neonatal progestin treatment was used to permanently inhibit adenogenesis and adult fertility. These studies revealed a narrow and well-defined window in which progestin treatments induced permanent infertility by impairing neonatal gland development and establishing endometrial changes that result in implantation defects. These model systems are being utilized to better understand the molecular mechanisms underlying uterine adenogenesis and endometrial function. The ability of neonatal progestin treatment in sheep and mice to produce infertility suggests that an approach of this kind may provide a contraceptive strategy with application in other species. Recent studies have defined the temporal patterns of adenogenesis in uteri of neonatal and juvenile dogs and work is underway to determine whether neonatal progestin or other steroid hormone treatments might be a viable contraceptive approach in this species.
Animal Reproduction Science, 2018
This research assessed the developmental stages and morphological quality of dog embryos collected during different stages of pregnancy as well as the relationship with serum progesterone recorded at insemination and embryo collection. Embryos were collected from 23 young mature bitches, that had been inseminated with fresh semen 3 to 6 days after the LH surge (day 0). Embryo flushing was performed on pregnancy days 8 to 11 (Group 1), 12 to 15
REPRODUCTION, 2010
In pigs, endometrial functions are regulated primarily by progesterone and placental factors including estrogen. Progesterone levels are high throughout pregnancy to stimulate and maintain secretion of histotroph from uterine epithelia necessary for growth, implantation, placentation, and development of the conceptus (embryo and its extra-embryonic membranes). This study determined effects of long-term progesterone on development and histoarchitecture of endometrial luminal epithelium (LE), glandular epithelium (GE), and vasculature in pigs. Pigs were ovariectomized during diestrus (day 12), and then received daily injections of either corn oil or progesterone for 28 days. Prolonged progesterone treatment resulted in increased weight and length of the uterine horns, and thickness of the endometrium and myometrium. Hyperplasia and hypertrophy of GE were not evident, but LE cell height increased, suggesting elevated secretory activity. Although GE development was deficient, progestero...
Biology of Reproduction, 2012
Uterine gland development (adenogenesis) in mice begins on Postnatal Day (PND) 5 and is completed in adulthood. Adenogenesis depends on estrogen receptor 1, and progesterone (P4) inhibits mitogenic effects of estrogen on uterine epithelium. This progestin-induced effect has been used to inhibit uterine gland development; progestin treatment of ewes for 8 wk from birth has produced infertile adults lacking uterine glands. The goals of the present study were to determine if a window of susceptibility to P4-mediated inhibition of uterine gland development exists in mice and whether early P4 treatment abolishes adenogenesis and fertility. Mice were injected daily with P4 (40 lg/g) or vehicle during various postnatal windows. Adenogenesis, cell proliferation, and expression of key morphoregulatory transcripts and proteins were examined in uteri at
Theriogenology, 2017
This article describes the effects of MPA use on the canine uterus using stereological methods. Entire reproductive tracts were removed from normal healthy canine bitches (Canis lupus familiaris) and grouped as: nulliparous (n ¼ 11), multiparous (n ¼ 11) and MPA-treated (n ¼ 11; nulliparous; two treatments; 5 mg/kg). 1 cm samples were cut from the corpus, horn and uterine tube and fixed in 10% formaldehyde. Sections of each were mounted on slides and stained with hematoxylin-eosin. We assessed the fraction area for components of endometrium and myometrium and V V (volume density) and S V (surface density) of the gland and stroma using the M 36 test system provided by the STEPanizer Stereological Tool. No gross histological differences were observed between study groups in the uterine tube, uterine corpus and horn. The wall of the uterine corpus and horn in MPA-treated bitches was characterized as being thicker than in the other groups. A cross-section of the uterine corpus revealed no differences between components of uterine wall in the corpus and horn; however, differences were observed in the volume density [V V ; %] in variables such as: V V[str.vasc/uterus] (nulliparous vs. multiparous; p ¼ 0.0019) and V V[str.supravasc/uterus] (multiparous vs. nulliparous and MPA; p ¼ 0.0035). In the endometrial gland, differences were detected in S V[gland/endom] (multiparous vs. MPA, p ¼ 0.0442). In the uterine horn, differences were only observed in the variable V V[lumen.gland/endom] (multiparous vs. MPA; p ¼ 0.0019). This study shows quantitative changes in the architecture of the endometrium and myometrium in all the uterine segments, mainly morphological endometrial gland changes of the uterine corpus, increasing the surface area per unit of volume; however, these changes usually do not differ quantitatively from those observed in the uterus of multiparous bitches.
Molecular Reproduction and Development, 2005
In ewes, the uterine gland knockout (UGKO) phenotype is caused by neonatal exposure to norgestomet to arrest uterine gland development and produce an adult which has a uterus characterized by the lack of endometrial glands. Since endometrial glands in the sheep produce the lymphocyte-inhibitory protein, ovine uterine serpin (OvUS), an experiment was conducted with ewes of the UGKO phenotype to evaluate whether the inhibitory actions of progesterone on tissue rejection responses in utero are dependent upon the presence of endometrial glands. Control and UGKO ewes were ovariectomized and subsequently treated with either 100 mg/day progesterone or corn oil vehicle for 30 days. An autograft and allograft of skin were then placed in each uterine lumen and treatments were continued for an additional 30 days before grafts were examined for survival. All autografts survived and had a healthy appearance after histological analysis. Allografts were generally rejected in ewes treated with vehicle but were present for hormone-treated ewes, regardless of uterine phenotype. Analysis of the histoarchitecture and protein synthetic capacity of the uterus revealed that progesterone induced differentiation of endometrial glands and synthesis and secretion of OvUS in UGKO ewes. The UGKO ewes had reduced density of CD45R þ lymphocytes in the endometrial epithelium and there was a tendency for progesterone to reduce this effect in luminal epithelium. Taken together, results confirm the actions of progesterone to inhibit graft rejection response in utero. Responses of UGKO ewes to progesterone indicate that the hormone can induce de novo development and differentiation of endometrial glands, at least when skin grafts are in the uterus.
Progesterone and Placental Hormone Actions on the Uterus: Insights from Domestic Animals1
Biology of Reproduction, 2004
Progesterone is unequivocally required for maternal support of conceptus (embryo/fetus and associated extraembryonic membranes) survival and development. In cyclic sheep, progesterone is paradoxically involved in suppressing and then initiating development of the endometrial luteolytic mechanism. In cyclic and pregnant sheep, progesterone negatively autoregulates progesterone receptor (PR) gene expression in the endometrial luminal (LE) and superficial glandular epithelium (GE). In cyclic sheep, PR loss is closely followed by increases in epithelial estrogen receptor (ER␣) and then oxytocin receptor (OTR), allowing oxytocin to induce uterine release of luteolytic prostaglandin F2␣ pulses. In pregnant sheep, the conceptus produces interferon tau (IFN) that acts on the endometrium to inhibit transcription of the ER␣ gene and thus development of the endometrial luteolytic mechanism. After Day 13 of pregnancy, the endometrial epithelia do not express the PR, whereas the stroma and myometrium remain PR positive. The absence of PR in the endometrial GE is required for onset of differentiated function of the glands during pregnancy. The sequential, overlapping actions of progesterone, IFN, placental lactogen (PL), and growth hormone (GH) comprise a hormonal servomechanism that regulates endometrial gland morphogenesis and terminal differentiated function during gestation. In pigs, estrogen, the pregnancy-recognition signal, increases fibroblast growth factor 7 (FGF-7) expression in the endometrial LE that, in turn, stimulates proliferation and differentiated functions of the trophectoderm, which expresses the receptor for FGF-7. Strategic manipulation of these physiological mechanisms may offer therapeutic schemes to improve uterine capacity, conceptus survival, and reproductive health of domestic animals and humans.