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Department of Pharmacology, Case Western Reserve University School of Medicine (K.A.R., J.H.N.), Cleveland, Ohio 44106; and the Department of Anatomy, University of Maryland School of Medicine (A.N.H.), Baltimore, Maryland 21201
Address all correspondence and requests for reprints to: John H. Nilson, Ph.D., Department of Pharmacology, Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, Ohio 44106-4975. E-mail: JHN{at}PO.CWRU.EDU
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies in rodents have focused on the role of endogenous androgens in rodent sexual development. Administration of aromatizable androgens to immature rats has been shown to cause infertility (7), induce precocious vaginal opening (with or without ovulation) (8, 9, 10), cause ovarian cyst formation (11, 12), and result in "masculinization" of the hypothalamus (13). The applicability of these studies is limited by the use of exogenous androgens, however, and variable results are obtained depending on the type of androgen, dosage, delivery, or duration of treatment.
Recently, we described female mice that maintain chronically elevated
serum LH and androgens secondary to expression of a transgene encoding
a chimeric LH ß-subunit in pituitary gonadotropes (14). The chimeric
transgene included the bovine LHß gene (bLHß) ligated to the coding
sequence of the carboxyl-terminal peptide (CTP) of the hCG ß-subunit
(15). Targeted expression of the resulting coding sequence, bLHß-CTP,
was achieved by fusion to a well characterized, bovine 
-subunit
promoter (16, 17). The addition of the CTP was demonstrated to increase
the half-life of recombinant LH in the serum of rodents 2- to 3-fold
(14) and was used in transgenic mice to increase the likelihood of
achieving elevated levels of serum LH. Female bLHß-CTP mice exhibited
elevated serum LH and testosterone and an increased androgen/estrogen
ratio. Although polycystic ovaries represented the predominant ovarian
morphology seen in bLHß-CTP mice, other ovaries contained abundant
luteinized tissue or granulosa and thecal/interstitial cell tumors.
As hyperandrogenemia in bLHß-CTP mice is gonadotropin dependent and chronic, these animals represent an ideal model for studying the effects of elevated androgens on sexual development. Although our initial examination of bLHß-CTP mice was restricted to adults, we suspected that expression of the transgene might lead to elevated LH and androgens during the prepubertal period. To establish the pattern of LH hypersecretion and hyperandrogenism in the immature animal, we examined the hormonal and morphological changes associated with ovarian development in bLHß-CTP females from 2–6 weeks of age. Elevated LH and testosterone were present at 2 weeks of age and led to precocious vaginal opening and uterine enlargement. Chronically elevated LH and androgens resulted in accelerated follicular development and extensive thecal-interstitial hypertrophy, followed by the development of hemorrhagic, polycystic ovaries.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit
promoter (-315/+45) (16, 17). DNA was injected into oocytes from
(C57BL/6 x SJL)F1 mice and offspring typed by PCR using tail DNA.
Founder animals and subsequent male offspring were mated with CF-1
female mice. The mice described in these experiments were females from
the F4 and F5 generations. Animals were housed under controlled
temperature and constant light. Male and female pups were separated by
3–4 weeks of age but housed in the same room. Vaginal lavage was
performed each morning from the onset of vaginal opening until the
death of the animal at 5 weeks. Trunk blood and tissues were obtained
after animals were killed by CO2 gas. All animal studies
were approved by the institutional care and use committee of Case
Western Reserve University.
RIA
Steroid hormone RIA was performed using kits from Pantex (Santa
Monica, CA) that were validated in our laboratory for use with mouse
serum. The limit of detection for serum estradiol was 5 pg/ml, with an
intraassay coefficient of variability of 11.1%. The limit of detection
for serum testosterone was 0.1 ng/ml, with an intraassay coefficient of
variability of 10.5%. LH was assayed, as previously described, by the
Physiology Department at Colorado State University (18). The limit of
detection for serum LH was 0.104 pg/ml, with an intraassay coefficient
of variability of 5.8%. All measurements were performed with single
aliquots due to the small amount of serum available and were completed
in a single assay. Statistical differences of variances were evaluated
by ANOVA, reported as the mean ± SE, and
P < 0.05 was considered statistically significant.
Tissue sections
For ovarian sections, the ovary was rapidly removed after death
and placed in 4% paraformaldehyde for at least 1 h, followed by
further fixation in 10% formalin at 4 C. All tissues were embedded in
paraffin, sectioned, and stained with hematoxylin and eosin by the
Histology Core of the Department of Pathology, Case Western Reserve
University.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The pattern of gonadotropin secretion
in transgenic animals was the same as that in nontransgenic
littermates; LH secretion was maximal at 2 weeks of age, diminished
during weeks 3 and 4, and increased again by the fifth week, coincident
with the normal onset of puberty. Although gonadotropin secretion
diminished during weeks 3 and 4, LH levels in bLHß-CTP females
remained elevated above the levels associated with the initiation of
puberty in nontransgenic animals.
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). By day 14, most
transgenic mice had elevated testosterone, although the variability in
secretion at this point prevented the mean from being statistically
significant. In contrast, the levels of testosterone were significantly
elevated (3- to 5-fold over the control value) and relatively constant
over the remaining period. Serum estradiol was increased in bLHß-CTP females at the time of vaginal opening on day 21 [transgenic, estradiol, 28.1 ± 7.68 pg/ml (n = 7); control, estradiol below the detection limit, which was set at 5 pg/ml (n = 7); P < 0.05]. Estradiol concentrations remained below the detection limit of the assay (5 pg/ml) in 4- to 6-week-old nontransgenic animals. In contrast, serum estradiol levels were measurable in 4- to 6-week-old bLHß-CTP females, but wide variability and small numbers precluded significant differences compared with levels in nontransgenic animals.
Transgenic mice demonstrated signs of precocious puberty
The first indication that transgene expression was exerting an
effect on reproduction before puberty was the appearance of vaginal
opening in transgenic females 9 days before that in nontransgenic
animals. The early changes in the external appearance of the vagina in
transgenic mice were dramatic as the vaginal mucosa became swollen and
turgid. Vaginal opening was complete in transgenic mice by day
21.2 ± 0.15 (n = 9), but, on the average, did not occur
until day 29.7 ± 0.86 (n = 11; P < 0.01) in
nontransgenic controls.
In rodents, vaginal opening is usually concurrent with the first
ovulatory surge and is thought to be driven by estrogen (19). Uterine
growth is also dependent upon increased estrogen secretion, and the
uterus typically takes on a ballooned appearance due to fluid
accumulation and the trophic effects of estrogen immediately before the
first ovulation. When we examined the uteri from day 21 transgenic
females we observed grossly enlarged, fluid-filled uteri (Fig. 2). As expected, nontransgenic littermates had thin,
atrophic uteri without fluid accumulation at this early time.
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Transgenic mice demonstrate accelerated folliculogenesis and
polycystic ovaries
To determine whether precocious vaginal and uterine changes were
associated with advanced follicular development, we examined
histological sections of ovaries from weeks 1–6.
Ovaries from 1- and 2-week-old animals demonstrated similar follicular
development in both transgenic and nontransgenic mice (not shown).
These ovaries contained a large cohort of both primordial and early
growing follicles with granulosa layers two to four cells thick. At the
time of vaginal opening (week 3), however, advanced ovarian development
in transgenic mice was easily observed. Many follicles in nontransgenic
ovaries had developed small pockets of follicular fluid, indicating the
beginning of antrum formation; these follicles appeared to be
undergoing atresia (Fig. 3A). In contrast, bLHß-CTP
ovaries had several antral follicles, indicating advanced follicular
development (Fig. 3B). In addition, transgenic ovaries contained
distended, blood-filled vessels.
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, A and B). Atretic follicles were
recognized by characteristic morphological features. The granulosa
cells along the basement membrane were no longer elongated, but
resembled the "beads on a string" morphology previously described
in atretic follicles (20). There were numerous cells with pyknotic
nuclei, and apoptotic bodies were visible. In contrast, healthy
appearing antral follicles contained organized, elongated granulosa
cells with normal nuclei, evidence of cell division, and no loss of
cell-cell contact.
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). The thecal layer was also not
clearly delineated from the surrounding interstitial cells. In
nontransgenic mice, the interstitial cells were long and slender, and
organized around the outer granulosa layer, consistent with developing
theca (Fig. 5A). There was no evidence of corpora lutea.
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); however, transgenic ovaries contained
numerous follicles with very large antra typical of preovulatory
follicles (Fig. 3D). Several features of these large follicles were
abnormal, however. First, many follicles contained blood instead of
clear antral fluid. Second, in some follicles the granulosa cell layer
appeared disorganized, as the layer had been thrown into folds and
pulled away from the basal lamina (Fig. 6). There were
many sections of the granulosa cell layer that appeared to be breaking
apart or thinning. Despite the disorganized appearance of the granulosa
cell layer, few pyknotic nuclei or apoptotic bodies were seen, and the
oocytes often appeared fairly healthy, indicating that the unusual
follicles were not undergoing typical atresia. In several follicles,
eccentrically located oocytes were seen, with only a thin layer of
surrounding cumulus cells. Despite the presence of well developed
follicles, there was no evidence of corpora lutea at this point, and
many normal appearing follicles at all stages of development were
present.
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).
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). The walls of the
cysts contained diverse cytology, with variable morphology in different
regions of the same structure (Fig. 8). Some cysts were
thin walled and contained only slender, theca-like cells, whereas
others contained hypertrophied cells that may have been derived from
granulosa, theca, or both. Other cyst walls contained thick layers of
highly luteinized cells, reminiscent of secondary interstitial tissue.
As there is little evidence that ovulation occurs in transgenic
animals, these are probably not corpora lutea and may represent
luteinized, unruptured follicles. Despite the dramatic cystic changes,
growing follicles were still present in 5- and 6-week-old transgenic
ovaries. They were present largely in the periphery of the ovaries, as
the center was largely replaced by cystic tissue.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Expression of the bLHß-CTP transgene is initiated before 2 weeks of
age, as serum LH levels are dramatically elevated by this time.
Interestingly, serum LH levels in transgenic and nontransgenic mice
demonstrate similar variation, with the lowest levels observed at 3 and
4 weeks of age. In rats, this fall in serum gonadotropin levels has
been attributed to the maturation of the hypothalamic-pituitary-gonadal
axis. Specifically, it has been proposed that after day 15, estrogen
negative feedback replaces androgen feedback as the dominant mechanism
for suppressing gonadotropins (19), resulting in lower serum
gonadotropin levels. As the RIA in Fig. 1 does not distinguish mouse LH
from transgenic LH-CTP, it is not clear whether the drop in LH
concentration at 3 weeks represents suppression of both transgene and
endogenous LH secretion or merely suppression of mouse LH
secretion.
The coexistence of both elevated serum LH and elevated serum steroids
in transgenic mice suggests a relative insensitivity of transgene
expression to negative steroid feedback. This apparent resistance to
steroid suppression is unexpected, as previous in vivo
studies of the bovine promoter linked to a reporter gene in
transgenic mice revealed both estrogen and androgen suppression (21, 22). In addition, male transgenic mice expressing the bLHß-CTP
transgene did not exhibit elevated LH despite vigorous expression of
the transgene noted by immunostaining of gonadotropes (14). Therefore,
female mice expressing the bLHß-CTP transgene are unique in their
inability to appropriately regulate gonadotropin expression and prevent
chronically elevated LH. This may occur as a consequence of altered
development of the hypothalamic-pituitary-gonadal axis after perinatal
exposure to elevated androgen levels. For example, female rodents
treated with a single dose of testosterone during the perinatal period
become masculinized; they are unable to initiate LH surges in response
to estrogen compared with untreated females (13). Although this
masculinization has not been demonstrated in primates (23), perinatal
androgen exposure in girls is linked with disorders such as PCOS (5, 6). Girls with virilizing congenital adrenal hyperplasia have elevated
androgen levels at birth. Barnes et al. recently
demonstrated that at sexual maturity many of these women have elevated
serum LH, presumably as a result of an alteration of the sensitivity of
the hypothalamus and pituitary to negative feedback from sex steroids
(6).
The finding of hyperandrogenemia in bLHß-CTP females may be a physiological response to increased gonadotropin stimulation. However, this would contradict previous pharmacological studies in rodents that show desensitization of Leydig and luteal cells after stimulation with hCG (24). According to previous data, elevated LH would be expected to cause down-regulation of LH receptors and a blunted steroidogenic response. It is possible that this mechanism is ineffective in limiting steroid production in bLHß-CTP females. Further study of the number of LH receptors in transgenic ovaries and the steroidogenic response to gonadotropins is required to understand the molecular response to chronically elevated LH levels.
Hyperandrogenemia in bLHß-CTP females is associated with precocious sexual development. This was first noted by the appearance of vaginal opening 9 days earlier than nontransgenic control mice. The presence of increased testosterone and estradiol on day 21 suggests the mechanism for these precocious changes. In previous studies, administration of pharmacological doses of dehydroepiandrosterone to immature rats resulted in precocious vaginal opening and ovulation (9). This effect appeared to depend upon the aromatization of dehydroepiandrosterone to estrogen, as administration of a nonaromatizable androgen, dihydrotestosterone, did not lead to vaginal patency at any dose. Another group implanted SILASTIC brand capsules (Dow Corning, Midland, MI) containing testosterone to approximate physiological concentrations of androgens and observed precocious vaginal opening with no associated ovulation (10).
The latter study correlates well with the phenotype observed in bLHß-CTP females, as vaginal opening was not coupled to ovulation. The presence of estrous smears in transgenic animals at vaginal opening suggests a predominance of estrogen secretion. It is possible that an ovulatory surge may have occurred in transgenic females at 5 weeks of age, as luteinized follicles were observed in ovaries and diestrous smears appeared between 4–5 weeks of age. However, it is not at all clear that the presence of luteinized follicles is an accurate indicator of ovulation. For example, we did not examine the oviducts for ova, and our previous study of bLHß-CTP adults suggested that these animals were anovulatory. Therefore, luteinization may have occurred without a preovulatory LH surge. In summary, increased concentrations of androgens appear to stimulate vaginal opening, but do not lead to early ovulation in bLHß-CTP females.
The sustained increase in serum LH produced by the transgene is associated with the precocious development of preantral follicles into large, preovulatory follicles. This process is first evident by the appearance of nonatretic, antral follicles by week 3, when nontransgenic mice show evidence of widespread atresia in the largest, early antral follicles. In transgenic mice, these antral follicles continue to develop into tertiary follicles. Preovulatory-like follicles from 4-week-old bLHß-CTP follicles resembled normal antral follicles seen in 6-week-old nontransgenic females.
However, several abnormal morphological features were also observed in transgenic, preovulatory-like follicles. For example, there were regions of the granulosa cell layer that were thinned and disrupted, and numerous antra contained blood. By 5 and 6 weeks, the granulosa cells often appeared hypertrophied, as if becoming luteinized. Finally, these follicles do not undergo typical atresia as expected in the absence of a LH surge, but instead, in the presence of chronically elevated LH, they transformed into large hemorrhagic cysts.
The functional capacity of these abnormal follicles is unknown. For example, it is unclear whether preovulatory follicles in 3-week-old transgenic mice can ovulate in response to a gonadotropin surge or whether the oocytes will be capable of fertilization. Ovulation may be prevented by the lack of a gonadotropin surge in bLHß-CTP mice. Ovulation also requires the presence of LH receptors on granulosa cells of a mature follicle. Although it is not known whether the abnormal follicles of bLHß-CTP mice express LH receptors, the luteinized appearance of the granulosa cells and of some cyst walls suggests that they are present. Additional studies are necessary to determine the distribution of LH receptors, the onset of LH responsiveness, and the ability of the follicle to ovulate in response to a single pulse of hCG or PMSG.
A model of functional ovarian hyperandrogenism?
In addition to polycystic ovaries, ovarian disorders such as
hyperthecosis and ovarian neoplasms may be associated with
hyperandrogenemia in women. Therefore, Ehrmann et al.
introduced the concept that PCOS is one example of a larger group of
disorders that result in functional ovarian hyperandrogenism (FOH)
(25). The underlying abnormality in FOH is gonadotropin-dependent
hyperandrogenemia. Elevated intraovarian androgen levels may be caused
by a number of hormonal imbalances and associated with a spectrum of
ovarian phenotypes. In the development of FOH, there appears to be a
dysregulation of androgen secretion, such that the steroidogenic
pathway is excessively stimulated by a gonadotropin stimulus. This is
illustrated in women with PCOS by an exaggerated rise in androgen
precursors and androstenedione with a GnRH agonist stimulus.
Female mice expressing the bLHß-CTP transgene demonstrate gonadotropin-dependent hyperandrogenemia. The occurrence of elevated LH and testosterone in the serum of bLHß-CTP females may involve an insensitivity of the transgene to negative feedback and/or a lack of down-regulation of LH receptor-stimulated steroidogenesis at the level of the ovaries. Further studies are necessary to discern whether ovaries from transgenic mice demonstrate an exaggerated steroidogenic response to gonadotropins, as seen in women with FOH, or merely a physiological response to excess gonadotropins. The bLHß-CTP mice provide a unique opportunity to study the molecular mechanisms leading to pathological ovarian androgen production. Future studies will examine whether excess LH stimulation leads to dysregulation of androgen synthesis in the ovary and whether hyperandrogenemia in the immature animal predisposes the hypothalamic-pituitary-gonadal axis to inadequate negative steroid feedback.
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Acknowledgments |
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Footnotes |
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Received January 31, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4-androstenedione on the
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subunit gene by androgen
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despite the absence of a high affinity binding site for estrogen
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