(6)


Upsala J Med Sci 111 (2): 215–226, 2006

A Morphometric Study on the Endometrium of Rat Uterus in
Hypothyroid and Thyroxine Treated Hypothyroid Rats

1I.M.Inuwa and 2M.A. Williams 
1Dept of Human and Clinical Anatomy. Sultan  Qaboos University. Oman 2Dept of Biomedical

Science, Sheffield University, England

ABSTRACT

Hypothyroidism increases the rate of pregnancy loss. Other manifestations include
menstrual disorder, and infertility. Serum levels of gonadotropins are low in hypot-
hyroid patients. Though studies of uterine ultrastructure are well established as
approaches to investigating the pathophysiology of infertility, they have scarcely
been extended to the study of hypothyroid related infertility. The present study inve-
stigates the effect of hypothyroidism on the ultrastructure of uterine epithelium. 

Three groups of Wistar rats were studied. Two groups were initially made hypot-
hyroid using methimazole, and the third group was an untreated control. One hypot-
hyroid group was given daily injections of thyroxine for six weeks. The uteri were
removed in all three groups, and processed for transmission electron microscopy
and morphometry. It was found that absolute epithelial cell volume was decreased
in hypothyroidism. The volume of the nucleus had decreased though its relative
volume in the cell had increased. The height of the luminal epithelium in hypothy-
roid rats also decreased by (33.8%) as compared with controls. Basement membra-
ne thickness was significantly increased in hypothyroidism. The changes were all
substantially abrogated by the administration of thyroxine. 

This study suggests that thyroid hormones might be importantly concerned in the
maintenance of the normal structure of uterine epithelial cells.

INTRODUCTION

It is well known that human hypothyroidism is almost always associated with sub fer-
tility (1). Hypothyroid women are known to have difficulty in getting pregnant (2-3).
Furthermore, should a hypothyroid individual get pregnant, successful conclusion of
pregnancy is difficult there being a high risk of both abortion, and still birth in such
mothers (4-5). Gonadotropin profiles in hypothyroid women have been extensively

215

Received 2 December 2004
Accepted 17 June 2005



investigated (6-7). Most findings have demonstrated a decrease in the serum level of
FSH and LH (8-9). Based on this observation. It has generally been believed that the
reason for infertility in hypothyroid women was anovulation, as there is poor ovarian
stimulation by the pituitary gland (10). However, until recently the structure of the
hypothyroid uterus had been little studied. The study of uterine epithelial morphology
has importance since for implantation to occur, there has to be a process whereby the
fertilised ovum and the surface epithelium interact. This necessitates the epithelium
being adequately prepared for pregnancy. Indeed, surface epithelial structure had been
shown to determine the success of implantation (11). IT has been reported previously
that methimazole-induced hypothyroidism caused gross changes to the histology of the
uterus (12). These alterations could functionally translate into an inability of the uterus
to maintain pregnancy, and hence explain why abortion is common in hypothyroidism.

The aims of this study were to establish via morphometric methods whether Hypothy-
roidism had any effect on the ultrastructure of rat uterine luminal epithelium.

MATERIAL AND METHODS

Animal model
Hypothyroid Wistar rat was used as a model for the study. Hypothyroidism was cre-
ated by oral administration of 0.02% Methimazole in the drinking water (12-13)
Two groups (A and B) were initially made hypothyroid, with one group, (B), recei-
ving exogenous thyroxine intraperitoneally after hypothyroidism was established. A
third control group. (C), of normal rats was maintained on tap water. Daily vaginal
smears were obtained from rats in all groups to determine the stage of the oestrus
cycle. The animals were six weeks old at the start of treatment and were killed after
a further six weeks. Each rat was killed by an intraperitoneal overdose of anaesthet-
ic (xylazine and ketamine hydrochloride in ratio of 1:2 v / v) before removing the
uterine horns.

Tissue processing
One horn from each rat was randomly selected and cut transversely into three equal
portion. Each portion was further chopped into pieces of about 1 mm3 and then
fixed in 2.5% phosphate buffered glutaraldehyde (pH 7.24) for 1 8 hours at 4°C.
The fixed pieces were briefly washed in phosphate buffer ( pH 7.2 ) dehydrated in
ascending concentrations of ethanol up to and including dried absolute ethanol. The
dehydrated tissues were then immersed in propylene oxide for 20 minutes with one
change followed by infiltration in a mixture of Araldite and propylene oxide (ratio
1:1) for 30 minutes. The infiltrated tissues were then dropped into pots containing
fresh 100% Araldite resin and left to polymerise at 60° for 48 hours (14). The tis-
sues were embedded in this way so as to ensure randomness in orientation of the tis-
sue when sections were obtained. This was achieved by letting the tissue sink to the
bottom of the embedding moulds unaided. Blocks were selected, and trimmed, and

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semi-thin sections (t = 0.5�m) obtained on a Reichert-Jung ultramicrotome (JX
301). These were stained with Toluidine Blue and examined under a light micro-
scope (Leitz Laborlux K). A ribbon of ultra-thin sections was then cut using a dia-
mond knife (Diatome MX 3776). The sections were expanded with chloroform
vapour, and those producing silver-grey interference colour were picked up on
200�m mesh copper grids (Gilder), stained with uranyl acetate, followed by lead
citrate (15).Electron micrographs were taken on cut film with a Philips 301 trans-
mission electron microscope operated at an accelerating voltage of 60 kv. Micro-
graphs used for morphometric estimates were taken at a nominal magnification of
x1300. A micrograph of a cross-grating replica (2160 /mm) was included in each
negative series as a magnification standard.

Sampling protocol
A systematic random sampling procedure was carried out in order to obtain a repre-
sentative sample of tissue from each group of animals (16). Six animals were used
in each group. In an earlier pilot experiment, using a two-way ANOVA we had
established that there was no significant difference in structure between the two
horns of the same rat, and between the various regions of the same horn (12). One
horn from each rat was randomly selected and cut transversely into three equal por-
tion. Each portion was further chopped into pieces of about 1 mm side and
processed into Araldite blocks for TEM. From each animal, three blocks were
selected by lottery (one block per portion). From each block a ribbon of silver sec-
tions was obtained and examined under a transmission electron microscope. A raster
of systematic random fields of view was obtained on the microscope and six micro-
graphs per block were taken. From each rat six micrographs were selected by lot-
tery (two from each block), and measurements carried out.

Morphometry
Morphometric analysis was performed on electron micrograph negatives viewed
under a projecting microscope at x13 magnification. An overlay screen bearing an
array of points was randomly applied onto the projected image, and the number of
points hitting various components of the cell were counted and used to estimate vol-
ume densities (Vv). Epithelial cell height was measured on profiles showing the
whole epithelium from basement membrane to the luminal surface taking into con-
sideration the micrograph magnification. The volume-weighted mean volume of
epithelial cell nucleus was estimated b\ the point-sampled intercept method (17-18).
A random array of test points was superimposed on the electron micrograph nega-
tives. Where a point hit a nuclear profile, a line which crossed the profile was drawn
through the point at a randomly selected angle. This was repeated for all nuclear
profiles hit by the test points. The part of the line which intercepted the nuclear
membrane was measured (l).Each intercept was then raised to the power of 3 (l3) 
and the mean (l3) was calculated. This mean nuclear intercept length was used to
estimate the nuclear volume thus;

217



The major (a) and minor (b) axes of the epithelial nuclear profiles were also mea-
sured, and the mean diameter (d) obtained from

The axial ratio     of the nucleus was also calculated (19). Absolute volume V, of the
average epithelial cell was estimated using the volume density, Vv, and volume
weighted mean volume of the nucleus    using the formula;

Harmonic and arithmetic mean thickness of epithelial basement membrane as measured
using the orthogonal intercept method (20-21). Micrograph negatives containing slices of
the luminal epithelium were projected at a final magnification of x12744. This image was
overlaid with random test lines that made chance intersections with the basement mem-
brane surface. Taking the plasmalemmal side of the basement membrane as the horizon-
tal, a line was drawn at 90˚ (orthogonal) through the intersection point towards the outer
edge of the basement membrane. The lengths of these orthogonal intercepts were mea-
sured using a logarithmic ruler. These, together with the number of observations, were
used to estimate ‘harmonic mean’ thicknesses of the basement membrane, t

h
(20-21). All

variances were computed and expressed on a ‘between animal’ basis. Analysis of differ-
ences in absolute cell and organelle volumes, epithelial height, and basement membrane
thickness between animal groups was performed using the non-parametric Mann-Whit-
ney-U test. In each case, the null hypothesis was rejected if the probability of no differ-
ence was found to be less than 5% (i.e. P < 0.05). All statistical computations were made
using the Instat statistical package, version 1.15 (Graphpad Softwares, 1990) run on a
personal computer.

RESULTS

Ultrastructure of normal uterine horn luminal epithelium in the rat
Luminal epithelial cells in uterine horn of control rats were more or less uniform. They
were columnar shape sitting on a thin basement membrane, and having clear cut cell
borders as shown in Figure 1A. The nucleus, placed one third of the way up the cell,
was ovoid and mainly euchromatic with a prominent nucleolus. It was about one fourth

218



219

of the length of the cell (axial ratio 3.1). Cytoplasm was rich in rough endoplasmic
reticulum, with a few lipid droplets situated mainly in the infranuclear region. The
luminal surface had numerous slender microvilli with a few electronlucent vesicles just
beneath them. Giant autolysosomes were present occasionally in the infranuclear
regions of the cells.

Ultrastructure of hypothyroid rat uterine horn luminal epithelium
As shown in Figures 1B and 2B epithelia from uterine horn in hypothyroid rats were
also columnar and lay on a thicker basement membrane than that below normal epithe-
lia (Fig 2A). Nuclei were also ovoid, mainly euchromatic and with a prominent nucleo-
lus. The nuclei were about one half of the cell height, and were situated in the bottom
halves of the cells. Lipid droplets were abundant in the cytoplasm and were situated
both in the supranuclear and infranuclear regions. Rough endoplasmic reticulum was
scanty. Microvilli appeared shorter than in euthyroid epithelia. All the epithelial struc-
tural changes observed were less pronounced in hypothyroid rats given thyroxine.

Figure 1. (A) Uterine horn luminal epithelium in control rat. Notice the giant autolysosomes (long
arrow) typical of oestrus stage, and a thin basement membrane (arrow head). Nucleus (n).
(B) Uterine horn luminal epithelium in hypothyroid rat. The cells were shorter, with a much thicker
basement membrane (arrow head) as compared to euthyroid epithelia. Autolysosomes are absent 



Estimated parameters of normal rat uterine horn luminal epithelium
The mean absolute volume of a luminal epithelial cell (cv % in parentheses) was
1235.50 (17.5) �m3 with a mean height of 35.14 �m (18.2). Volume weighted mean
volume of the nucleus was 222.39 (21.6) �m3 and the nuclear/cytoplasmic ratio was

220

Variable Control MMI MMI+T4
Epithelial Height
( m)

35.14*
(18.2)

23.42
(12.4)

27.81*
(18.5)

Nuclear/Cytoplasmic
ratio

0.22*
(19.9)

0.35
(15.7)

0.26*
(19.5)

Nuclear profile
diameter ( m)

7.18
(16.7)*

6.27
(20.9)

6.47
(14.3)

Nuclear profile Axial
ratio

3.1
(14.8)

2.9
(27.9)

2.8
(18.5)

‘Harmonic mean’
basement membrane
thickness (nm)

143.86*
(25.5)

252.93
(18.1)

184.52*
(16.9)

Arithmetic mean
basement membrane
thickness (nm)

187.53*
(3.9)

272.07
(9)

232.96*
(8.6)

*p<0.05 vs hypothyroid rats

Tabell 1. Mean and coefficient of variation (CV%) of volumetric parameters of different compart-
ments of the uterine horn luminal epithelium in euthyroid (control), hypothyroid (MMI) and thyroxine
treated hypothyroid rats (MMI+T4).

Figure 2. (A) High power view of the basement membrane (BS) in euthyroid rat luminal epithelium.
Notice the lamina lucida (open arrow) and the reticular lamina (RT) Lipid droplet (L).
(B) High power view of the basement membrane (BS) in hypothyroid rat luminal epithelium. Notice
the increase in thickness.



0.22 (19.9). Mean volume fraction of nucleus in the cell was 0.18 (21.6) whilst that of
mitochondria in cytoplasm was 0.061 (19.5), and lipid droplets 0.03 (33.8). Harmonic
basement membrane thickness was 143.86 (25.5) nm. Mean nuclear diameter was 7.18
(16.7) �m with an axial ratio of 3.1 (14.8) (see Tables 1 and 2)

Changes in parameters of the luminal epithelium in hypothyroid rats
Changes in volumetric and other parameters in hypothyroid rat uterine horn luminal
epithelia are illustrated in Tables 1 and 2. The absolute volume of the average epitheli-
um was reduced by 72.4% in hypothyroid (MMI) animals as compared to euthyroid
(control) animals, whilst in hypothyroid rats given thyroxine the decrease was by 48%.
Nuclear volume decreased by 60.1% and 39.3% in hypothyroid, and hypothyroid rats
given thyroxine respectively. However, the volume density of nucleus in the cell was
increased significantly in hypothyroid rats as compared with euthyroid ones. Total vol-
ume of lipid droplets, was increased by 4.5% in hypothyroid as compared with euthy-
roid rats. There was no increase in lipid volume in hypothyroid rats given thyroxine.
Mitochondrial volume density was unchanged in all three groups, though its absolute
volume had decreased by 72.8%. in hypothyroid (MMI), and by 48% in hypothyroid
rats given thyroxine. The difference in parameters between hypothyroid rats given thy-
roxine (MMI+T4) and those not given (MMI), was significant at p<0.05 (see Table 1).
Nuclear-cytoplasmic ratio was significantly higher in hypothyroid rats as compared
with euthyroid ones. Basement membrane thickness was increased by 75.8% in
hypothyroid, as compared with euthyroid rats. This increase however, was by 28.3% in
hypothyroid rats given thyroxine when compared with euthyroid animals. Height of
luminal epithelium had decreased by 33.3% in hypothyroid (MM1) as compared with
euthyroid (control) rats. in hypothyroid rats given thyroxine (MMI+T4) the decrease

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Compartment Volume densities Vv Absolute volumes V ( m
 3
)

Control MMI MMI+T 4 Control MM! MMI+T4
Nucleus 0.18*

(21.6)
0.26
(18)

0.21*
(23)

222.39*
(21.6)

88.55
(17.2)

134.90*
(23.3)

Mitochondria 0.061
(19.5)

0.060
(15.1)

0.060 (12.5) 75.36*
(19.5)

20.43
(15.1)

39.18*
(12.5)

Lipid droplets 0.029*
(33.8)

0.11
(13)

0.053*
(18.6)

35.83*
(33.8)

37.46
(13)

34.04*
(18.6)

Whole cell 1235.50*
(17.5)

340.57
(14.4)

642.38*
(15.1)

* = P<0.05 vs hypothyroid rats.

Tabell 2. Mean and coefficient of variation (CV%) of morphometric parameters for uterine horn lumi-
nal epithelium in euthyroid (control) hypothyroid (MMI) and thyroxine treated hypothyroid rats
(MMI+T4).



was by 20.8%. The diameter of epithelial nuclei was greater in euthyroid than in
hypothyroid rats (p<0.05) though the mean nuclear axial ratio was not significantly dif-
ferent in all three groups (see Table 2).

DISCUSSION

This study has demonstrated the occurrence of significant structural change in the
uterine horn luminal epithelium in hypothyroidism. Such change was decreased by
thyroxine administration. The improvement in epithelial morphometric parameters
effected by exogenous thyroxine administration to hypothyroid rats in this study.
suggests that in healthy animals the presence of the hormone helps maintain normal
epithelial structure. This correlates with the clinical experience which demonstrated
that thyroxine administration helped correct menstrual irregularities in hypothyroid
women (22-23) Similarly, in pregnant hypothyroid women thyroxine administration
improves the outcome. The decrease in cell size, nuclear volume. and mitochondrial
volume in hypothyroid animals could be thus a direct effect of thyroxine depriva-
tion, particularly since thyroid hormone is believed to exert its influence on cells by
facilitating the transcription of DNA and hence new protein synthesis. Indeed, the
rat uterus has been shown by Evans et al. (25) and Mukku et al. (26) to contain thy-
roid hormone receptors suggesting that it is a specific site for thyroid hormone
action. Absence of the hormone could thus slow down the epithelial metabolic
processes resulting in a decrease in cell and nuclear volumes as well as a decrease
in mitochondrial volume. The fact that this study demonstrates in hypothyroid uter-
ine epithelia a decrease in nuclear size apparently without alteration of shape further
suggests that there may be a decrease in nucleic acid transcription in the nuclei of
these cells. An increase in nuclear-cytoplasmic ratio coupled with a decrease in total
cell volume in hypothyroid animals suggests that the cytoplasmic volume was far
more reduced than was the nuclear volume. As the basement membrane is com-
posed of collagen (including type IV), and a number of glycosaminoglycans, an
increase in its thickness suggests that hypothyroidism influences the turnover of
these components. Harvey et al. (27) have shown that hypothyroidism is associated
with a significant decreased collagen breakdown. Others (28-30) have reported
increased deposition of collagen type IV in tissues from hypothyroid individuals.
The apparent increase in collagen and glvcosaminoglycan deposition in hypothy-
roidism is thus probably not due to an increase in synthesis, but to a decreased
breakdown of these substances (31). Since the thickness of basement membrane is
known to be inversely proportional to the rate of diffusion of substances across that
membrane (32), the increase would be expected to impair diffusion to the basal
aspect of the cells. This would be of particular relevance with respect to large mole-
cular weight substances such as hormones, enzymes etc. Impaired diffusion of such
control substances is likely to result in altered metabolism and probably impaired
morphology, which might explain the generalised decrease in cell size observed

222



here. Similarly, an increase in basement membrane thickness might well adversely
affect specific epithelial function as in the case of medical conditions such as
glomerulonephritis. in fact, there are also reports in the literature of hypothyroidism
being associated with basement membrane damaging glomerulonephritis (33-34).
Hypothyroidism is known to increase the serum levels of lipids and cholesterol in
humans. It also causes excessive deposition of fat under the skin (35). The present
study shows that extra lipid accumulation occurs within the uterine epithelium sug-
gesting that hypothyroidism may influence generally cellular lipid metabolism. The
fact that the observed changes in epithelial structure in this study were similar to
those found during dioestrus stage of the oestrus cycle in rats by Spornitz et al. (36)
further suggest that hypothyroidism affects ovarian steroid hormone metabolism.
Therefore, alteration in steroid hormone levels during hypothyroidism is especially
likely since the dioestrus stage in rats is characterised by low steroid hormone lev-
els, and the hypothyroid rats in this study had a preponderance of dioestrus vaginal
smears (12). However, it could also be claimed that the changes we have seen might
have been due to another indirect effect of hypothyroidism on gonadotropins, since
it has been shown that hypothyroidism leads to a decrease in the serum levels of the
pituitary gonadotropins FSH and LH (8, 37-38). This could in turn lead to a
decrease in ovarian stimulation and hence a decrease in ovarian steroid hormone
levels, causing a decrease in uterine epithelial stimulation resulting in the structural
changes observed in this study.

In conclusion, it seems reasonable to suggest that though the rarity of pregnancy
in hypothyroid women has generally been passed off as due to a high incidence of
anovulation (39), the observations made here suggest, that in addition epithelial
structural change might be present contributing an adverse affect by making interac-
tion with fertilised ovum less successful. Similarly, altered steroid hormone metabo-
lism in hypothyroidism could disturb an existing pregnancy. Study of ovarian histo-
chemistry in hypothyroidism, particularly investigation of the activity of steroid
synthesising enzymes are indicated and these may prove important since proges-
terone deficiency is well known to result in infertility, or during pregnancy to abor-
tion.

ACKNOWLEDGEMENTS

This work was carried out with sponsorship from the University of Sheffield. We
wish to thank Messrs John Proctor and Mick Turton for the micrography work.

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Corresponding author: Dr IM Inuwa
Department of Human and Clinical Anatomy.
Sultan Qaboos University
Muscat. Oman
Tel: (00968) 24141176
Fax:(00968) 241431175
Email: Ibrahim1@squ.edu.om

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