Cellular and molecular regulation of the primate endometrium: a perspective

Abstract

This contribution will trace some of the many seminal studies on the female uterus (endometrium) over the centuries and conclude with a description of some current research initiatives in our laboratory. Numerous contributions from many investigators over the years have contributed to our current understanding of endometrial function. The historical section of this chapter is intended to be a brief overall description of some of these efforts and not exhaustive. Additional information can be found in the review articles and books cited herein.

Figure 1

The earliest surviving illustration of uterine anatomy (9^th century). The drawing was based on the studies of Soranus of Ephesus [1].

Figure 2

A drawing of the cavity of the uterus with fetus in situ by Leonardo da Vinci (15^th century). In this beautiful drawing, the rim of the placenta and a coil of the umbilical cord can be seen [1].

Figure 3

A photograph of Edgar Allen [3] who together with Adelbert Doisy identified "oestrin" (estradiol) as the hormone that promoted sexually maturity in the female rhesus monkey.

Figure 4

A manuscript by the brilliant scientist and humanist G.W. Corner, the discoverer of progesterone, that summarizes studies on menstruation during the first half of the 20^th century [10].

Figure 5

The innovative studies of Markee that used intraocular implants of endometrium in the rhesus monkey to study menstruation [11]. This work began in 1928 and was completed in 1938.

Figure 6

Studies by Bartelmez on the histological paramenters of the rhesus monkey throughout the menstrual cycle. [12]. These studies defined histological zones in the endometrium. Note that the collaborators include George.W. Corner and Carl G. Hartman.

Figure 7

Sketch that depicts the procedure used by Hartman to study endometrial regeneration [15]. These studies demonstrated that in the absence of visible endometrial mucosa regeneration still occurred.

Figure 8

Tritiated estradiol was used as a tracer by Jensen and Jacobsen to study in vivo uptake and retention in the rat [20]. This classic study helped to establish the presence of estrogen receptors in target tissues.

Figure 9

A depiction of estrogen receptor interaction almost 25yrs ago (left panel) [19] and a current view of estrogen receptor interactions (right panel) [23,25].

Figure 10

Immunohistochemical analysis of the estrogen receptor in the rhesus monkey endometrium (left panel) and myometrium (right panel) with appropriate controls below. These studies in Brenner's laboratory were the first in the rhesus monkey endometrium [31] and demonstrated that immunoreactive estrogen receptor resided primarily in the nuclear compartment.

Figure 11

Demonstration that immunoreactive estrogen receptor was dramatically reduced by progesterone treatment in the rhesus monkey endometrium [37]. The top left panel shows the absence of estrogen receptor staining in the endometrial functionalis after estrogen plus progesterone. The other panels monitor the return of estrogen receptor immunoreactivity during progesterone withdrawal (days 1–7).

Figure 12

Rhesus monkey implantation site one date after implantation as described by Allen Enders [49]. ICM (inner cell mass).

Figure 13

A schematic representation together with examples of relative gene expression patterns in the rhesus endometrium during the secretory phase [56]. A) progesterone (P) repression of estradiol (E)-dependent genes. B) autologous down-regulation of P-dependent genes e.g. fragment 10. C) P-induction of genes during the secretory phase e.g. fragment 5. D) P-induction of gene expression during the window of receptivity e.g. fragment 12, syncytin. E) a composite cascade of gene expression patterns A-D. The associated panel (B-D) for each fragment shows the relevant temporal portion of the gel following PCR analyses.

Figure 14

SLPI expression and hormonal levels of progesterone (P) during the expected window of receptivity in the rhesus monkey endometrium [56]. Upper panel shows the hypothetical expression pattern (red line) and the associated temporal pattern of SLPI expression as determined by PCR analyses. The lower panel shows the associated serum progesterone levels during this timeframe.

Figure 15

Semiquantitative PCR analysis comparing Inadequate (IA) and Adequate (A) cDNA populations on cycle days 13, 17, 21, 23, and 26 for SLPI and WFDC2 (panels A and B respectively) [66]. Lane M is a size marker (100 bp DNA ladder). The side panels compare IA and A cDNA populations on day 23 (midsecretory phase) for each gene and the column charts represent average densitometric analysis of three experiments and margin of error (SD).

Figure 16

Semiquantitative PCR analyses of endometrial cDNA populations for syncytin and BAT2 (panels A and B respectively) prepared from Inadequate (IA) cycle days 13, 17, 21, 23, and 26 [66]. The side panels compare IA and Adequate (A) cDNA populations on day 23 for each gene. The column charts represent average densitometric analyses of three experiments with margins of error (SD).

Figure 17

Laser capture microdissection of rhesus monkey endometrial glands [67]. Top left panel shows the laser etching of glands, top right panel shows the glands removed by the capture film, and the bottom panel shows the glands captured on the film.

Figure 18

Semiquantitative PCR analysis of cDNA populations prepared from laser capture microdissected rhesus monkey endometria from adequate secretory phases [66]. Basalis stroma (BS), basalis glands (BG), functionalis stroma (FS) and functionalis glands (FG) were analyzed for 18S rRNA, SLPI, WFDC2 and BAT2 panels A, B, C and D respectively.