The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 873-877
Copyright © 2000 by The Endocrine Society
Ovarian Hyperthecosis in the Setting of Portal Hypertension
Phyllis W. Speiser,
Myron Susin,
Hironobu Sasano,
Stuart Bohrer and
James Markowitz
Departments of Pediatrics (P.W.S., J.M.), Pathology (M.S.), and
Surgery (S.B.), North Shore University Hospital, New York University
School of Medicine, Manhasset, New York 11030; and Department of
Pathology (H.S.), Tohoku University School of Medicine, 980-8575
Sendai-Shi, Japan
Address correspondence and requests for reprints to: Phyllis W. Speiser, M.D., Division of Pediatric Endocrinology, North Shore University Hospital, 300 Community Drive, Manhasset, New York 11030. E-mail: speiser{at}nshs.edu
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Abstract
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Hepatocellular dysfunction and perturbed portal hemodynamics alter
steroid metabolism. Men with liver disease have gynecomastia, although
women similarly affected rarely show virilization. We report a
10-yr-old girl with portal hypertension and shunting associated with
precocious puberty and ovarian hyperandrogenism. This was one of
premature twin girls; neither had clitoromegaly or genital ambiguity.
In one child, neonatal respiratory problems led to umbilical vein
catheterization with subsequent development of portal hypertension.
Pubic hair was first noted at age 6 yr, breasts at 7 yr, and severe
acne and clitoromegaly at 10 yr. Baseline sex hormones were elevated:
androstenedione (A), 413 ng/dL; testosterone (T), 226 ng/dL; and
estradiol (E2), 160 pg/mL. Liver transaminases were within
the normal range, however, the coagulation profile was mildly abnormal.
Cosyntropin adrenal stimulation revealed no steroidogenic defect.
Dexamethasone suppression reduced A and T slightly. LH-releasing
hormone stimulation produced a pubertal rise in LH and FSH.
Pelvic sonography showed a large right ovary with numerous follicles.
Surgical exploration revealed symmetrically enlarged ovaries with dense
capsules. Histology of ovarian wedge resections showed hyperthecosis;
immunohistochemistry showed stromal cells expressing steroidogenic
enzymes and proteins. One month postoperatively, A and T were unchanged
from baseline, whereas E2 decreased to 56 pg/mL. A single
dose of depot leuprolide acetate significantly reduced T. Subsequent
treatment with oral contraceptives reduced T to 50 ng/dL, and cyclical
menses occurred. We conclude that precocious puberty and ovarian
hyperthecosis were induced in this young girl by elevated circulating
levels of sex hormones, a consequence of portasystemic shunting and
impaired hepatic steroid metabolism.
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Introduction
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STEROID hormones are catabolized
principally via hepatic reduction, oxidation, and hydroxylation;
steroid metabolites are thereafter excreted mainly in urine as
glucuronidated or sulfated conjugates (1). Hepatocellular dysfunction
and perturbed portal hemodynamics clearly alter steroid metabolism. The
disease model most extensively studied is advanced cirrhosis of the
liver. Men with this disease often are feminized with gynecomastia,
female escutcheon and body habitus, and reduced testicular mass (2).
Animal studies suggest that portasystemic shunting, and not portal
hypertension per se, accounts for the hormonal abnormalities
observed (3, 4). These include reduced metabolic clearance and
prolonged half-life of cortisol (5), aldosterone (6), and testosterone
(T) (7). In contrast, the excess estrogen found in patients with liver
disease is due in large part to increased conversion from adrenal
and/or ovarian precursors, such as androstenedione (A) (7). Such
changes are attributable to alterations in the relative activities of
various hepatic steroid-metabolizing enzymes (8). Sex steroids that
escape the normal enterohepatic circuit intact may interfere with the
hypothalamic-pituitary-gonadal axis (9). Additionally, portasystemic
shunting can alter central neurotransmitter synthesis, secretion, and
turnover, another mechanism interfering with normal GnRH and
gonadotropin secretion and further disturbing the balance of sex
hormones.
There have been few reports of women with hepatic disease showing
virilization. In one case report, a middle-aged woman with chronic
active hepatitis presented with virilization due to ovarian
hyperthecosis (10); ovariectomy resulted in amelioration of her
symptoms. A woman with documented portasystemic shunting had
hyperestrogenemia and ultimately developed a hepatic adenoma,
attributed to prolonged high-level estrogen exposure (11). Autoimmune
chronic active hepatitis and cirrhosis were found in association with
severe hyperandrogenism and a sonographic picture of polycystic ovaries
in another case (12). Finally, there has been an abstract report of
childhood portal vein thrombosis associated in two young women, aged 17
and 23 yr, with hyperandrogenemia and polycystic ovaries (13).
We report this case because of the unusual association of portasystemic
shunting associated with excessive circulating sex hormone levels in a
young girl causing both estrogenic and androgenic symptoms, including
precocious puberty and virilization.
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Case Report
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A 10.5-yr-old Caucasian girl presented for evaluation of
precocious puberty characterized by early pubic hair and breast
development and recent onset of acne. Her past medical history was
notable for portal hypertension and shunting of the portal circulation.
The child was the 28 weeks, 938-g product of an uncomplicated twin
gestation; the presence of a single placenta identified the girls as
identical twins. There was no clitoromegaly or genital ambiguity at
birth. Neonatal problems included respiratory distress, assisted
ventilation, and umbilical vein catheterization. Subsequently, she
developed presinusoidal portal hypertension and esophageal varices.
Pubic hair was first noted at 6 yr of age, and breasts at 7 yr of age.
At age 7.5 yr evaluation showed an advanced wrist bone age of 10 yr,
parabasal cell predominance on vaginal maturation index, a prepubertal
pattern of gonadotropins following LH-releasing hormone (LHRH)
stimulation, and bilateral small ovarian follicles. No treatment or
further evaluation was given, and the patient was lost to endocrine
follow-up for the next 3 yr, during which time her main problems
centered on hepatic shunting with resultant bleeding esophageal
varices.
At 10 yr of age the patient developed severe acne and was treated with
Retin-A and tetracycline. Because of her history of a
bleeding diathesis and her advanced state of pubertal development, she
was again referred to endocrinology to decide how to manage her
incipient menses. The patient was taking ranitidine, a histamine
H2-receptor blocking agent to reduce gastric acid production, and
atenolol, a cardioselective ß-blocking agent to reduce blood
pressure. On physical examination at 10.5 yr, her height was more than
97% and here weight was 95%. Blood pressure was normal, and
there were no Cushingoid features. She had Tanner IV breasts and pubic
hair; the clitoris was markedly enlarged to 3 x 1.5 cm. Moderate
facial acne was noted.
Bone age x-ray of the left wrist was now further advanced to 14 yr.
Hepatic biochemical profile was normal with 21 U/L serum
glutamic-oxaloacetic transaminase, 13 U/L serum glutamic-pyruvic
transaminase, 114 alkaline phosphatase, 3.6 mg/dL albumin, and 0.9
mg/dL total bilirubin. The coagulation profile showed mildly elevated
pro-time and activated partial thromboplastin time. Baseline
afternoon serum sex hormone levels were elevated beyond the range of
normal for adult women (Endocrine Sciences, Inc.
Laboratory, Calabassas Hills, CA): A, 413 ng/dL; T, 226 ng/dL; and
estradiol (E2), 160 pg/mL. Sex hormone-binding
globulin was normal at 2.3 µg/dL. Neither ranitidine nor atenolol is
known to increase sex hormone levels. Mullerian-inhibiting hormone was
normal at 2.8 ng/mL (normal range in girls aged 10–12 yr is 2.5–8.8;
Ref. 14). Fasting insulin was elevated at 28 µU/mL, with a
simultaneous blood glucose of 66 mg/dL. Insulin-like growth factor I
(IGF-I) was normal at 201 ng/mL (normal range for 10-yr-girls is
123–330). Urinary 17-ketosteroids and 17-hydroxycorticosteroids were
in the normal range (2.9 and 1.7 mg/g creatinine, respectively).
Cosyntropin adrenal stimulation revealed no steroidogenic defect.
Dexamethasone suppression (2 mg/day for 2 days) reduced A and T
slightly (Table 1
). LHRH stimulation
produced a pubertal rise in LH and FSH (33 and 9.8 mIU/mL,
respectively). The serum human CG level was less than 3
µIU/mL. Pelvic sonography showed a large right ovary (volume 12.5 mL)
with numerous follicles; the left ovary was normal in size and
character (volume 2.8 mL). Because of the extreme elevations of sex
hormones, and the large right ovary, the diagnosis of juvenile
granulosa cell tumor was considered likely.
Surgical exploration, performed 4 months after her presentation with
clitoromegaly and markedly elevated androgens and estrogens, revealed
symmetrically enlarged ovaries with dense capsules. No tumor was
apparent, and bilateral wedge resections were performed. Histology
showed hyperthecosis (Fig. 1) with foci
of luteinized stromal cells with clear cytoplasm. The degree of stromal
cell hyperplasia was minimal. Well-developed ovarian follicles with
membrana granulosa and theca interna, along with some atretic follicles
were detected. No hilar cell hyperplasia was seen. Immunohistochemistry
was performed for Ad4BP (adrenal binding protein 4, also termed
steroidogenic factor 1, SF-1), P450scc, 3ß-HSD, and P450c17 as
described (15, 16). Ad4BP immunoreactivity was detected in the nuclei
of almost all luteinized, or enzymatically active, and some
nonluteinized stromal cells (Fig. 2A),
hilar cells, granulosa, and theca cells, including those in atretic
follicles and stromal cells without morphologic evidence of steroid
synthesis. P450scc, 3ß-HSD, and P450c17 were also detected in the
cytoplasm of almost all these cells, however, P450c17 immunoreactivity
was most pronounced and widely distributed (Fig. 2B).
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Figure 1. A, Light photomicrograph showing a portion
of ovary with capsular thickening (hematoxylin and eosin;
magnification, x125). B, Light photomicrograph showing ovary with
stromal hyperthecosis and nests of luteinized cells (hematoxylin and
eosin; magnification, x500).
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Figure 2. A, Nuclear immunoreactivity of adrenal
binding protein 4 detected in the ovarian stromal cells. B, P450c17
immunoreactivity detected in cytoplasm of luteinized, enzymatically
active, stromal cells. Brownish stain indicates protein
of interest in each case.
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Table 1
shows hormone values before and after surgery. One month
postoperatively, A and T were unchanged from baseline, whereas
E2 decreased to 56 pg/mL. A single dose of depot
leuprolide acetate (15 mg) reduced T by more than 50%. Subsequently,
the patient was treated with a triphasic oral contraceptive (Ortho
Tri-Cyclen; Ortho-McNeil Pharmaceutical Corp., Raritan, NJ). This therapy produced a further reduction in serum T
(to 50 ng/dL) and allowed initiation of controlled regular menses. She
has done well, maintaining normal T and A levels for the past year on
this treatment. Hepatic biochemical profile has remained normal, to
date.
There was no family history of hirsutism, polycystic ovaries,
infertility, diabetes mellitus, or related endocrinological
problems.
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Discussion
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Ovarian stromal hyperthecosis is a relatively uncommon disorder in
young women, and even rarer among adolescents (17), although the
original report of this condition was in an 18-yr-old with hirsutism
and oligomenorrhea (18). Grossly, such ovaries are large with thick,
smooth, and sclerotic capsules. Unlike typical polycystic ovaries,
these organs lack subcapsular cysts. Histological examination reveals
clusters of luteinized stromal cells with high lipid content and
eosinophilic cytoplasm (10, 19). Clinical features include hirsutism,
menstrual irregularities, clitoromegaly, baldness, acne, and voice
changes. It has been suggested that hyperthecosis represents a late
stage of polycystic ovarian syndrome (20).
The pathophysiology of hyperthecosis remains obscure. Several
investigators have found evidence of a genetic predisposition to this
disease (21, 22, 23, 24). Ovarian tissue from women with this condition has
increased 17
-hydroxylase (25), but not aromatase (26), expression,
and activity, thus explaining the increased ovarian androgen production
(27). Immunohistochemistry performed on tissue sections from our
patient showed similar findings. In addition, AD4BP (or SF-1), an
essential transcriptional factor for steroidogenesis, as well as for
the development of the hypothalamic-gonadal axis (28), was also highly
expressed in our patient’s ovary, including luteinized and
nonluteinized stromal cells. Expression of these proteins associated
with steroid synthesis is especially unusual in normal stromal cells
(29) and is consistent with increased steroidogenesis in this ovary.
Steroid 17-hydroxylase is known to be regulated by both LH and IGF-I
in cultured theca cells (30). Thus, it is interesting to note that
ovaries with hyperthecosis have increased numbers of IGF-I receptors
(31). Furthermore, transgenic mice overexpressing LH manifest a
syndrome similar to polycystic ovaries in women (32).
This case provides insight into a novel mechanism in the
pathophysiology of polycystic ovarian syndrome and hyperthecosis
(i.e. variable hepatic metabolism of sex hormones). Evidence
suggesting a link between the portosystemic shunt and the development
of hyperthecosis includes the temporal sequence of events, the
biochemical profile of high serum sex hormones and low urinary steroid
hormones typical of adults with hepatic dysfunction, and the fact that
the identical twin sister had no precocious puberty and no evidence of
hyperthecosis. In our young patient, presumably, alterations in sex
hormone metabolism due to portasystemic shunting resulted in elevated
levels of both androgen and estrogens of adrenal origin. Unbound sex
hormones then probably interacted with the hypothalamus and pituitary,
inducing precocious puberty. We speculate that chronic bioactive LH
excess stimulated ovarian androgen and estrogen production and induced
pathological changes in the ovaries. Random serum levels of IGF-I,
IGF-BP3, GH, and thyroid hormones, as well as basal and LHRH-stimulated
immunoactive gonadotropins, however, were normal. Interestingly, a
fasting insulin level was high in our young patient. Both basal and
glucose-stimulated insulin levels are significantly higher in women
with hyperthecosis compared with controls (33). Furthermore, high
bioactive LH levels in hyperthecosis correlate with insulin levels,
although basal immunoactive gonadotropin levels are normal (33).
The clinician’s job of differentiation between hyperthecosis and
androgen-producing ovarian tumors is difficult. The marked elevation in
serum T and E2 and the apparent selective
enlargement of the right ovary on the pelvic sonogram suggested a
juvenile granulosa tumor, and, therefore, surgery was performed. Other
diagnostic considerations in this setting might include luteoma, Leydig
cell hyperplasia or tumors, thecoma, lipoid cell, small cell, or germ
cell ovarian tumors (34). Although Mullerian-inhibiting hormone is a
useful marker in mature granulosa cell tumors (35), this has not been
universally true in the juvenile form of these tumors (36).
Effective long-term treatment for hyperthecosis has not been
established. Early therapies included either bilateral oophorectomy or
wedge resection. The former procedure leaves patients with no recourse
for biological offspring, and the latter is of limited or transient
efficacy (17, 23, 37). In contrast, treatment with a long-acting
gonadotropin-releasing hormone agonist has been reported as an
effective adjunct to ovulation induction (37). We observed a clear
reduction in serum T after a single dose of depot leuprolide acetate.
We chose not to continue this therapy in our patient to avoid inducing
osteoporosis and other menopausal effects. Instead, we elected to treat
with a low estrogen triphasic oral contraceptive, which has been
effective in reducing androgen levels. Because insulin is implicated in
the genesis of hyperandrogenism in women with both polycystic ovaries
and hyperthecosis, other therapeutic considerations for overt insulin
resistance would include drugs such as a nonhepatotoxic
thiazolidinedione or metformin.
We conclude that precocious puberty and hyperthecosis were induced by
elevated circulating levels of sex hormones, a consequence of
portasystemic shunting that caused impaired hepatic steroid
metabolism.
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Acknowledgments
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We thank Dr. David MacLaughlin for measuring MIS, Drs. Robert
Scully and Robert Young for reviewing the pathology slides, and Drs.
Jean Wilson and Maria New for helpful discussions.
Received August 16, 1999.
Revised October 7, 1999.
Accepted October 27, 1999.
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Abstract
Introduction
