Reproductive processes in female mammals are characterised by cyclic alterations in the female tract and in sexual receptivity. The recurrent period of receptivity, or "heat" is called Estrus. The Estrous cycle has been most extensively studied in laboratory rodents (mice and rats). Rats kept separate from males in the laboratory repeat the Estrous cycle throughout the year at intervals of about five days, unless subjected to pregnancy, pseudo-pregnancy (after a sterile mating), or disease. The cycle involves the whole of the reproductive tract, and it is possible to determine the sexual status of the female rat by examination of smears prepared from the vaginal fluid.
Rats and mice are examples of polyestrus mammals (as are cats which are seasonally polyoestrus). Monestrus forms (most wild animals - foxes, bears, wolves etc.) complete a single estrous cycle annually. In the wild, rats and mice probably suspend the cycle for a period during the winter; the reproductive organs are in a state of quiescence, called anestrus.
(More? There is further information in the Menstrual Cycle notes Estrous Cycle)
Page Links: Introduction | Some Recent Findings | Estrous table | Histological Features | Carnegie Stages Comparison | Estrous Spelling | WWW Links | References | Glossary
Bilinski MJ, Thorne JG, Oh MJ, Leonard S, Murrant C, Tayade C, Croy BA. Uterine NK cells in murine pregnancy. Reprod Biomed Online. 2008 Feb;16(2):218-26. Review.
"Murine uterine natural killer (uNK) cells are transient, short-lived, terminally differentiated lymphocytes found in decidualized endometrium. ....Activated uNK cells are now considered critical for appropriate endometrial angiogenesis in early implantation site development and in non-gestational endometrium."
Bachelot A, Binart N. Corpus luteum development: lessons from genetic models in mice. Curr Top Dev Biol. 2005;68:49-84. Review.
"The life span and function of the corpus luteum is regulated by complex interactions between stimulatory (luteotrophic) and inhibitory (luteolytic) mediators. ... In rodents, prolactin is the major luteotrophic hormone by maintaining the structural and functional integrity of the corpus luteum for several days after mating. Other factors involved in steroidogenesis, control of cell cycle, apoptosis, and tissue remodeling have been shown to play a role in corpus luteum development and maintenance. Especially, PGF2alpha seems to be the most potent luteolytic hormone."
Deb K, Reese J, Paria BC. Methodologies to study implantation in mice. Methods Mol Med. 2006;121:9-34.
"....The process of implantation can be postponed and reinstated experimentally by manipulating ovarian estrogen secretion. Stromal decidualization can also be induced experimentally in the hormonally prepared uterus in response to stimuli other than the embryo. ...This chapter describes the routine laboratory methodologies to study the events of early pregnancy, with special emphasis on the implantation process in mice."
|
Stage |
Ovary |
Uterus |
Vagina |
Smear |
|
Diestrus |
Small follicles only are present with large corpora lutea from the previous ovulation. These secrete for only a very short time unless pregnancy or pseudopregnancy intervene. |
Small and anaemic, low motility, lumen small and slit-like. Cells of the uterine mucosa columnar; polymorphonuclear leucocytes in stroma; endometrial glands collapsed, atrophic. |
Epithelium thin, mitotic figures infrequent. Leucocytes abundant in stroma, migrate through the epithelium into vaginal lumen. |
Stringy mucous in which are entangled many leucocytes and a few nucleated epithelial cells. |
|
Proestrus |
Some follicles grow rapidly. |
Become more vascular, water content increases, organ distends. Contractility more pronounced. Epithelial cells become higher (continuing into estrus). Leucocytes disappear from mucosa. Endometrial glands hypertrophy. |
Epithelum thickens, numerous mitoses in inner layers. Old layers of epithelium line the lumen. Leucocytes no longer migrate through the epithelium. Superficial epithelial cells slough off into lumen. |
Largely small, round, nucleated epithelial cells, singly or in sheets. None to few leucoytes. |
|
Estrus |
Ovulation in the rat is spontaneous and occurs about 10 hours after the beginning of estrus. "Heat" (receptivity) lasts about 13 hours. Usually 10-20 eggs ovulated each time. |
gains maximum vascularisation. Epithelial cells reach maximum development. No leucocytes. |
Outer layer of epithelial cells become cornified and sloughed into the lumen. In early estrus these cells retain their nuclei, but in later stages no nuclei visible and the cells are irregular, flat, cornified plates. The skin around the vaginal orifice becomes swollen. |
Contains hundreds of large cornified cells (squames) with degenerate nuclei. Towards the end of estrus the smear becomes "cheesy" - masses of adherent cornified cells. |
|
Metestrus |
Many corpora lutea, which secrete only for a very short time, and small follicles. |
Epithelium continues vacuolar degeneration and replacement. Leucocytes in stroma. Decrease in size and vascularity. |
Deeper layers of the estrous epithelium now line the lumen, the older, superficial layers having become cornified and sloughed off. Reduction of mitotic activity in epithelium. Leucocytes in stroma and migrating through the epithelium into the lumen. |
Many leucocytes and a few cornified cells. |
For more detailed histological information see Champlin etal., 1973.
Uterus
The changes in the uterus may not be particularly well-marked.
1. Histological changes in the luminal epithelium
2 Histological changes in the glandular epithelium
3. Secretory activity of uterine glands
4. Changes in stromal cells, e.g. number of leucocytes
5. Overall changes in the size distention and shape of the lumen.
Vagina
Note the changes in the vaginal epithelium.
1. The number of mitotic figures
2. The number of layers in the epithelium
3. The amount of cornification, and the changes from live to dead cells.
4. Surface mucus coating the epithelium
5. Presence or absence of infiltrating polymorphonuclear leucocytes.
Vaginal Smears
Relate the appearance of the smears to the sections of the vagina, noting particularly the composition of cells in the smear and the vaginal epithelium.
1. Relative numbers and appearance of cell types - epithelial and polymorphs.
2. Presence of mucus.
Data For Carnegie Stages Comparison Graph (Species/Days) |
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|
Species |
Stage |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Days |
20 |
22 |
24 |
28 |
30 |
33 |
36 |
40 |
42 |
44 |
48 |
52 |
54 |
55 |
58 |
|
|
Days |
9 |
9.5 |
10 |
10.5 |
11 |
11.5 |
12 |
12.5 |
13 |
13.5 |
14 |
14.5 |
15 |
15.5 |
16 |
|
|
Days |
10.5 |
11 |
11.5 |
12 |
12.5 |
13 |
13.5 |
14 |
14.5 |
15 |
15.5 |
16 |
16.5 |
17 |
17.5 |
|
Table References
Human - O'Rahilly, Early human development and the chief source of information on staged human embryos. Eur. J. Obstet. Gynec. Reprod. Biol. 9 p273 (1979)
Mouse - Theiler, The house mouse. Springer-Verlag, NY (1972)
Rat - Witschi, Growth. Altman and Dittmer (ed), Fed. Soc. Exp. Biol., Washington (1962)
Internal: Mouse Stages | Mouse Timeline | Detailed Mouse Timeline | Mouse Estrous Cycle | Mouse Heart |
External: University of California, Irvine - University Laboratory Animal Resources Mouse Breeding Techniques
Links: Reviews | Articles | Online Textbooks | Search Textbooks | Search PubMed | Glossary
Search Feb 2006 "estrous cycle" 58093 reference articles of which 3911 were reviews.
Search PubMed: mouse estrous cycle | estrous cycle | mouse anestrus | oestrous cycle
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a disintegrin and metalloproteinase - (ADAM) a large family (-8, -9, -10, -12, -15 and -17) of secreted proteins suggested to be involved in remodelling mouse uterine tissue during the oestrous cycle.
anestrus - lack of a normal estrus cycle.
Bruce Effect - pheromones from a strange male can prevent embryo implantation in recently bred female.
calling behaviour - vocalization, vocal communication sounds associated with reproductive behaviour in several species.
Lee-Boot Effect - female mice housed together (in groups) results in a synchronization of their estrus cycles. In addition, the extended absence of male pheromones leads to a state of anestrus (lack of a normal estrus cycle).
major urinary proteins - (MUPs) proteins which carry volatile substances, including pheromones, and protect them during their internal passage (liver to kidneys into urine).
pheromone - a secreted chemical in sweat or urine that causes specific physiological response in other members of the same species.
Whitten Effect - female mice either singly or housed together (in groups) can be induced into estrus by exposure to male mouse urine or their dirty bedding.
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The estrous cycle is applicable to many different species, not just the mouse reproductive cycle.
The estrous cycle differs from the menstrual cycle seen in humans.
The mouse being a laboratory animal used in reproductive studies it is important to understand the natural reproductive cycle of the female mouse. This page includes a table outlining the major histological changes seen in the mouse during the estrous cycle.
Spelling Note: When searching both American (estrous) and British (oestrous) spellings are used in the literature (More? American and British Spelling Variations). My thanks also to Prof Jill Becker for correcting an obvious spelling error on this page "The adjective is spelled with a 'u' after the o. 'Estrus' refers to the stage of the cycle and is the noun form of the word."
Please email Dr Mark Hill if you wish to make a comment about this current project.