Blockage of gonadotropin-induced first ovulation
caused by thyroidectomy and its possible mechanisms in
rats
Kazuhiro
Tamura1,
Minoru
Hatsuta1,
Gen
Watanabe2,
Kazuyoshi
Taya2, and
Hiroshi
Kogo1
1 Department of Pharmacology, Tokyo University
of Pharmacy and Life Science, Hachioji, Tokyo 192-0392; and
2 Department of Veterinary Physiology, Tokyo
University of Agriculture and Technology, Fuchu, Tokyo 183, Japan
 |
ABSTRACT |
To determine the role of the thyroid gland on
the ovarian functions during the initiation process of puberty, we
examined the effects and its mechanisms of hypothyroidism on the first ovulation induced by equine chorionic gonadotropin (eCG) in immature female rats. Animals were thyroidectomized on day 22 and were injected with 5 IU of eCG on day 26 to induce the first
ovulation on day 29. The number of antral follicles that
secrete inhibin and the ovarian weight were significantly increased in
thyroidectomized rats (Tx rats) 48 h after eCG treatment compared with
those in non-Tx rats. However, thyroidectomy (Tx) significantly
suppressed the rates of ovulating animals on day 29. The
blockage of ovulation in Tx rats was recovered by administration of
human chorionic gonadotropin or luteinizing hormone (LH)-releasing
hormone (LHRH) on day 28. Inhibition of serum LH (not
follicle-stimulating hormone) levels induced by Tx was almost restored
to control levels by injection of LHRH. A significant increment in
prolactin levels in Tx rats was also observed on day 28. The
present data indicate that Tx before puberty in female rats causes the
blockage of the first ovulation and that the inhibitory effects on
ovulation are mainly due to the reduction in the preovulatory LH surge,
which is partially mediated through an inhibition of LHRH action on the
secretion of LH.
thyroid function; preovulatory luteinizing hormone; inhibin; prolactin
 |
INTRODUCTION |
THE DIRECT OR INDIRECT
relationship between the thyroid gland and reproductive
organs has been documented on the basis of in vivo and in vitro studies
(25, 34). Hypothyroidism is closely associated with the changes in
folliculogenesis and the formation of corpus luteum in rats, and
thyroid dysfunction causes disorders in ovarian functions in women.
When mature female rats are thyroidectomized, estrous cycles become
irregular and their ovaries become atrophic (25). It has been shown
that the response of ovaries to human chorionic gonadotropin (hCG) was
enhanced in hypothyroid rats, and ovaries turned into large cystic
forms (5, 13). A single injection of equine chorionic gonadotropin
(eCG) in prepubertal rats induces the first ovulation between 9 and 12 h after autonomous ovulatory luteinizing hormone (LH) surge, which
occurs ~57 h after eCG treatment (10). In our previous study,
thyroidectomy (Tx) in eCG-primed immature rats markedly stimulated the
secretion of ovarian hormones at least until 48 h after eCG treatment
(36). In eCG-primed thyroidectomized rats (Tx rats), the number of
mature follicles, which were ovulated by an injection of hCG at a dose comparable to the physiological LH dose at the ovulatory LH surge, was
significantly increased by ~75% at 33 h after eCG treatment compared
with control (eCG-treated non-Tx rat). In the present study, we
examined the effects of hypothyroidism on the eCG-induced first
ovulation in immature rats. In addition, serum concentrations of
gonadotropin, prolactin, and inhibin were measured to determine whether
the effects were accompanied by changes in the levels of pituitary or
ovarian hormones. We show here, together with the possible mechanisms,
that prepubertal hypothyroidism results in the blockage of the first
ovulation induced by a single injection of eCG.
 |
MATERIALS AND METHOD |
Animals.
Immature female rats of the Wistar strain were maintained under
controlled temperature (23 ± 1°C) and humidity (55 ± 5%) and a 12:12-h light-dark lighting schedule (lights on at 0700), with free
access to laboratory rodent chow and water. Tx was performed under
ether anesthesia at 22 days of age.
Drug treatment and experimental schedule.
To induce earlier puberty, immature rats were injected subcutaneously
with 5 IU eCG (Teikoku Hormone, Tokyo, Japan) dissolved in 0.2 ml
saline at 0800 at 26 days of age. To examine ovarian responsiveness to
gonadotropin for the first ovulation, 10 IU hCG (Teikoku Hormone) were
injected intraperitoneally at 1700 on day 28. To examine
pituitary responsiveness to luteinizing hormone-releasing hormone
(LHRH), 1 µg of LHRH (National Institute of Diabetes and Digestive
and Kidney Diseases, National Hormone and Pituitary Program) was
injected intravenously at 1600 on day 28. Blood samples were
collected via the abdominal aorta under ether anesthesia at 0800 on
day 28 for prolactin and at 1700 on day 28 for
gonadotropins and inhibin. Blood was allowed to clot at 4°C. Serum
samples were separated by centrifugation and stored frozen at
80°C
until assay for each hormone. The occurrence of ovulation on day
29 was determined by examining whether oocytes were present in the
ampulla of oviducts, using a dissecting microscope.
RIA of LH, follicle-stimulating hormone, inhibin, and prolactin.
Concentrations of gonadotropins, inhibin (35, 41), and prolactin (37)
were determined by RIA as previously reported. The intra- and
interassay coefficients of variation were 8.6 and 9.8% for LH, 5.7 and
20.4% for follicle-stimulating hormone (FSH), 5.1 and 11.0% for
inhibin, and 9.8 and 20.6% for prolactin, respectively.
Immunohistochemistry of inhibin.
To evaluate the immunohistochemical localization of inhibin,
paraffin-embedded ovarian sections were stained using antisera against
inhibin
-subunit, as previously reported (31). Briefly, sections in
which endogenous peroxidase activity was quenched by incubation with
3% H2O2 in methanol were incubated with Block Ace (Dainippon Pharmaceutical, Osaka, Japan) to prevent nonspecific reactions. Sections were incubated with a polyclonal antibody against
inhibin
-subunit at 37°C overnight. Polyclonal rabbit antibody to
inhibin was developed against Tyr30-labeled inhibin
-chain-(1
30) conjugated to rabbit serum albumin. Subsequently,
sections were incubated with 0.5% biotinylated goat anti-rabbit
secondary antibody (ABC-peroxidase staining kit; Vector Laboratories,
Elite, CA) and then treated with 2% avidin-peroxidase complex for 30 min at 37°C. Sections were reacted with 0.5% 3, 3'-diaminobenzidine
tetrachloride (Sigma) and 0.01% H2O2 to
visualize the bound antibody. Serial sections of ovaries at 48 h after
eCG treatment were exposed to normal rabbit serum instead of inhibin antibody or to preabsorbed antibody that had been incubated with 100-fold excess of bovine inhibin (32 kDa) at 37°C overnight to establish the specificity of inhibin antibody.
Statistical analysis.
Data are presented as means ± SE of n, no. of animals. The
significance of the difference was tested with an unpaired Student's t-test or Cochran-Cox test (2-tailed). Analysis of variance
followed by Tukey's multiple range test was employed in experiments
requiring multiple comparisons. Differences of P < 0.05 were
considered statistically significant.
 |
RESULTS |
Effects of Tx on eCG-induced autonomous first ovulation and influence
of exogenous ovulatory hormones on first ovulation.
To examine the first ovulation in the Tx group, the occurrence of
ovulation was checked when the rats were 29 days old (72 h after eCG
treatment; Table 1). The number of
ovulating animals in the Tx-eCG group was decreased (40%), although
the number of oocytes in ovulating rats was the same as that in the
intact-eCG group. We then examined the effects of hCG or LHRH on the
suppression in the rates of ovulating animals in the Tx groups.
Injection of hCG and LHRH was performed at 1700 on day 28, that
is, around the time at which endogenous ovulatory gonadotropin surge
occurs (41), and at 1600 on the same day, which is considered to be just after "the critical period" in first proestrus (16).
Treatment with hCG or LHRH restored the rates of ovulating animals in
the Tx group up to >80%, although the ovulation was not completely recovered. There was no statistical difference in the number of ovulations per ovulating rat among all groups. Ovarian weight in the
Tx-hCG group was significantly larger than that in the intact group or
intact-hCG group.
Effect of Tx on eCG-induced follicular development.
To determine whether Tx influences the localization of inhibin as an
indicator of follicular development, ovarian sections were stained with
an antibody against inhibin
-chain (Fig.
1). Positive staining of inhibin
-subunit was seen in granulosa cells of developing follicles at all
stages, including primary to tertiary follicles at 0 h in both groups.
At 48 h after eCG treatment, immunostaining was also detected in
healthy and atretic follicles of various sizes. Some other cell types
(theca interna and interstitial cells) also showed a modest staining.
Antral follicles larger than 400 µm in diameter were increased in the
Tx group, and granulosa cells of the follicles also had a positive
staining. Tx significantly decreased the body weight on day 28, which is 6 days after operation compared with intact rats (Table
2). It is well known that attainment of a
critical body weight is necessary for normal puberty to occur (3, 8).
To determine whether the body weight in Tx animals influences the
occurrence of ovulation in the present model, we checked both body
weight in ovulating rats and nonovulating rats. The weight of the
animals that did not ovulate was almost the same as the weight of those
that ovulated (58 ± 1.7 vs. 56 ± 1.6 g, 72 h after eCG),
indicating that a decrease in the body weight in Tx rats played no role
in the blockage of ovulation. An increase in ovarian weight was
observed in the Tx-eCG group, whereas a decrease in uterine weight was
seen in this group on the same day compared with that in the intact-eCG
group.

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Fig. 1.
Immunohistochemical localization of inhibin -subunit in
thyroidectomized equine chorionic gonadotropin
(eCG)-primed rat ovaries. Thyroidectomy (Tx) and eCG treatment
were performed as described in Table 1. Ovaries were collected before
(0 h) or 48 h after eCG treatment. Serial sections were incubated with
inhibin -subunit antiserum. Bar represents 500 µm. All sections
were photographed at the same magnification. Ovaries that were removed
48 h after eCG treatment were incubated with preabsorbed antibody
(neutralization) or with normal rabbit serum (NRS) instead of
anti-inhibin antibody.
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|
Effects of Tx on the serum levels of gonadotropins, inhibin, and
prolactin 2 days after eCG treatment.
To confirm the effects of Tx on the secretion of gonadotropin and the
effects of LHRH on its levels, serum concentrations of LH and FSH were
measured at 1700 on day 28 (Fig.
2). Serum levels of LH and FSH in the
Tx-eCG group were significantly lower than those of control (intact-eCG
group) at 1700 on day 28. Treatment with LHRH on Tx animals
enhanced the serum concentrations of LH, but not FSH, up to control
levels. At the same time, the serum levels of inhibin in the Tx-eCG and
Tx-eCG + LHRH groups were higher than those in the intact-eCG group
(Table 3). We then examined whether the
suppression in preovulatory LH surge in the Tx-eCG group is associated
with the serum levels of prolactin. When serum levels of prolactin were
measured on the morning of first proestrus (day 28) before
gonadotropin surge (Fig. 3), the serum
levels of prolactin in the Tx-eCG group were 2.2-fold higher than those
in the intact-eCG group.

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Fig. 2.
Effects of luteinizing hormone-releasing hormone (LHRH) on the serum
levels of luteinizing hormone (LH; A) and
follicle-stimulating hormone (FSH; B) in thyroidectomized
eCG-primed rats. Tx and eCG treatment were performed as described in
Table 1. Treatment with LHRH (1 µg, iv) was carried out 56 h after
eCG treatment (at 1600 on day 28), and blood was collected 1 h
after LHRH injection. Each value shows the mean ± SE of 3-4
rats. *P < 0.05 and **P < 0.01, significantly
different from intact-eCG.
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Fig. 3.
Effects of thyroidectomy (Tx) on serum levels of prolactin in
eCG-primed immature rats. Tx and eCG treatment were performed as
described in Table 1. Blood was collected 48 h after eCG treatment (at
0800 on day 28). Each value shows the mean ± SE of 12 rats. ***P < 0.001, significantly different from
intact-eCG.
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 |
DISCUSSION |
Irregular menstrual cycles and amenorrhea are often induced in
hypothyroid female patients (25, 34). The relationship between
ovulation disorders, such as amenorrhea, menorrhagia, and luteal phase
insufficiency, and thyroid functions has been suggested in humans and
experimental animals. We recently showed that hypothyroidism induced an
elevation in serum inhibin and estradiol, together with an acceleration
in the growth of mature follicles, which are capable of ovulating on
day 28 by exogenous hCG injected on day 27 (33 h after
eCG treatment) in eCG-primed immature rats (36). Hypothyroidism
stimulated the expression of mRNA for inhibin, and the stimulation was
suppressed by thyroxine treatment up to control levels, suggesting that
thyroid hormone has a direct inhibitory action on ovarian inhibin and
estradiol secretion in gonadotropin-primed prepubertal rats. However,
in the previous study, it was not clarified whether the occurrence of
the spontaneous first ovulation at 3 days after eCG treatment was
affected by Tx or not. We then determined here the role of thyroid
hormone in the induction of the first ovulation and hormonal changes in
the process of ovulation. Our data demonstrated that Tx reduced the
number of ovulating rats, and that the Tx-induced blockage of ovulation
was mainly due to the suppression of preovulatory LH surge, because
additional treatment with hCG or LHRH significantly increased the rates
of ovulation.
Hypothyroidism has been shown to be associated with secondary
hyperprolactinemia (38), which significantly increases the frequency of
anovulation in patients. We observed the increased levels of prolactin
on the day of first proestrus (day 28) in Tx animals. Similar
to our results, there is evidence indicating that plasma prolactin
levels are high in Tx rats with high levels of plasma estrogen (32,
43). An increase in prolactin levels causes the inhibition of normal LH
levels in humans (9) and reduces the pituitary response to LHRH in rats
(26, 33). The inhibition of LHRH secretion mediated by the elevation of
prolactin levels may result in an impairment of preovulatory LH
secretion on day 28 in the present model. Administration of
LHRH on day 28 reversed the levels of serum LH up to control
levels, although the levels of serum FSH could not be recovered. The
inhibin levels in the Tx-eCG and Tx-eCG + LHRH groups on day 28 were significantly higher than control levels. Therefore, the
suppression of preovulatory FSH secretion and the levels of FSH after
LHRH treatment in Tx rats may be caused by high levels of peripheral
inhibin, because the extent of FSH secretion strongly depends on the
levels of circulating inhibin. Our results implicate that the
suppression of LH surge in the Tx-eCG group is probably generated by
the inhibition of LHRH secretion at the hypothalamus and/or the
decrease in pituitary responsiveness to LHRH for LH release.
Hypothyroidism resulted in an increase in the concentration of
vasoactive intestinal peptide (VIP) in the pituitary (24). Because
thyrotropin-releasing hormone (TRH; see Ref. 19) and VIP (1, 30) are
thought to be regulators for prolactin secretion, the increased levels
of VIP in the pituitary in addition to the increase in TRH in the
hypothalamus might result in an elevation of prolactin. It has also
been shown that corticotropin-releasing hormone (CRH), in which levels
were increased by thiouracil treatment (39) and prolactin (42), may be
an inhibitory factor for LHRH release at rat hypothalamus (6, 23).
Figure 4 represents a possible hormonal
mechanism for the blockage of ovulation in the eCG-primed immature Tx
animals. A decrease in circulating thyroid hormones causes the
elevation of pituitary prolactin levels, which is in part mediated by
increases in the levels of TRH, thyroid-stimulating hormone, CRH and VIP. The increase in prolactin levels may
inhibit LHRH secretion and/or LHRH action on LH secretion from
the pituitary. Furthermore, Tx directly enhances the secretion of
ovarian estrogen and inhibin as previously reported (36). Estrogen
suppresses LHRH levels at the hypothalamus by its negative feedback,
and inhibin blocks FSH release from the pituitary.

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Fig. 4.
Possible hormonal mechanism for changes in
hypothalamus-pituitary-ovarian axis in gonadotropin-primed hypothyroid
female rats. Open arrow, secretion; , stimulation; dashed arrow,
inhibition in normal prepubertal rats; and , increase and
decrease, respectively, induced by thyroidectomy. TRH,
thyrotropin-releasing hormone; CRH, corticotropin-releasing hormone;
TSH, thyroid-stimulating hormone; VIP, vasoactive intestinal peptide;
T3, triiodothyronine; T4, tyroxine; GH, growth
hormone; PRL, prolactin; E2, estrogen.
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|
Interestingly, in the previous study, all Tx animals were ovulated by
hCG treatment at 33 h after eCG treatment, and the number of oocytes
became 1.75-fold as great compared with control (36). In the present
study, at 48 h after eCG treatment, we also observed that Tx induced an
increase in the number of large healthy follicles and ovarian weight in
Tx rats. However, the number of oocytes that were ovulated by hCG
injection at 57 h after eCG treatment did not increase significantly.
We could not clarify the reason why the effect of Tx on the number of
oocytes in ovulating rats time dependently changes after eCG treatment.
It is known that transient hypothyroidism in immature male rats causes
an increase in testis size (12) and sperm production (11), and
excessive 3,5,3'-triiodothyronine (T3) administration
promotes Sertoli cell differentiation and reduces the period of the
cell proliferation (40). Our observations may indicate that Tx in
immature rats temporarily and abnormally accelerates
gonadotropin-induced follicular development and life span, that is, the
number of Graafian follicles with normal maturity has already started
to decrease around the time of preovulatory LH surge (57 h after eCG
treatment) in Tx rats. The elevated levels in prolactin during the
preovulatory period may also be associated with the reduction of
oocytes. It was shown that ovulation in perfused ovaries was inhibited
by prolactin treatment in rabbits (18) and that prolactin inhibited the
luteinization of granulosa cells in rats (2) and reduced the
steroidogenesis of the cells in humans (14) in vitro. Prolactin might
have directly suppressed the process of ovulation in the eCG + hCG
group of Tx rats and resulted in a decrease in the number of oocytes in
ovulating rats, although there was an increase in the number of antral
follicles that were morphologically observed. Twenty percent of Tx
animals did not ovulate, even when hCG or LHRH was administered. Such a
decrease in the number of ovulating animals as well as the number of
ovulations per ovulating rat might be related to Tx-induced
hyperprolactinemia, which inhibits the sensitivity of the ovary to hCG
and LH. In addition to the changes in prolactin levels, it is well
established that Tx results in a decrease in the synthesis and
secretion of growth hormone (GH; see Refs. 27, 29) and the gene
expression of GH-releasing factor receptor (28) in rat pituitary. GH
exerts numerous effects on ovarian differentiation through binding to
specific GH receptors in rat ovary (7). For example, GH stimulates
FSH-induced LH receptor synthesis (20, 21) and the activity of tissue
plasminogen activator (4) in granulosa cells, suggesting a role of GH
in ovulation events as a paracrine mediator. The ovary may fail to ovulate without the normal serum GH environment. Therefore, the partial
recovery of ovulation induced by hCG and LHRH in Tx rats may be brought
about by inevitable changes in serum GH levels caused by Tx.
Tx decreased the normal increase in uterine weight after eCG treatment,
although an elevation of estradiol occurred. It is known that
T3 potentiates estradiol-induced increases in the uterine weight (17, 22) via a mechanism involving cross talk with T3 receptor in the uterus (15), suggesting a
"permissive" role of T3 for estrogen action. This
result may imply that T3 is essential for the normal
uterine development induced by eCG in the presence of estradiol,
because we can assume that the levels of estradiol in both eCG and
Tx-eCG groups were high enough to induce the maximal response to
uterine weight.
In conclusion, the present study suggests that hypothyroidism inhibits
the first ovulation in eCG-primed immature female rats and that the
blockage of ovulation is mainly mediated through the inhibition of
preovulatory LH surge from the pituitary.
 |
ACKNOWLEDGEMENTS |
We are grateful to Dr. A. F. Parlow in the Hormone and Antisera
Center, Dr. P. F. Smith in the Hormone Distribution Program, and S. Greenhut in the National Hormone and Pituitary Program for
radioimmunoassay materials. We also thank S. Saida for critical proofreading and Dr. A. Tohei for constructive criticism of the manuscript.
 |
FOOTNOTES |
Address for reprint requests: H. Kogo, Dept. of Pharmacology, Tokyo
University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan.
Received 31 December 1997; accepted in final form 6 May 1998.
 |
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