The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 5 1685-1689
Copyright © 1999 by The Endocrine Society
From the Clinical Research Centers |
Increased Bioactive Luteinizing Hormone Levels and Bio/Immuno Ratio in Women with Hyperthecosis of the Ovaries: Possible Role of Hyperinsulinemia1
Manubai Nagamani,
Collins Osuampke and
Mae Ellen Kelver
Department of Obstetrics and Gynecology, Division of Reproductive
Endocrinology, University of Texas Medical Branch, Galveston, Texas
77555-0587
Address all correspondence and requests for reprints to: Manubai Nagamani, M.D., Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555-0587. E-mail:
mnagaman{at}utmb.edu
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Abstract
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Unlike women with polycystic ovarian disease, women with hyperthecosis
have normal or low immunoactive LH levels. They have severe insulin
resistance with marked hyperinsulinemia. Bioactive LH levels have not
been studied in these women. The purpose of this study was to
investigate 1) whether there is an increase in bioactive LH levels in
women with hyperthecosis of the ovaries and 2) whether hyperinsulinemia
has an effect on LH secretion. Six women with hyperthecosis of the
ovaries confirmed by histological examination were included in the
study. Six normal women in the midproliferative phase of the cycle
served as controls. All women were admitted to the Clinical Research
Center at 0800 h, and blood samples were obtained every 15 min for
6 h. All samples were assayed for LH by RIA and bioassay. The PC
Pulsar Program was used for pulse analysis of LH secretion. Patients
with hyperthecosis had significantly higher (P <
0.002) bioactive LH levels (66.9 ± 13 mIU/mL) than controls
(29.3 ± 6 mIU/mL). Immunoactive LH levels in hyperthecosis were
not significantly different from those in control women. Significantly
higher bio/immuno LH ratios (P < 0.001) were
observed in women with hyperthecosis (6.2 ± 0.9) than in normal
control women (2.4 ± 0.5). There was a significant positive
correlation between insulin levels and the bio/immuno ratio of LH.
Pulse amplitude and interpulse intervals for immunoactive LH in
hyperthecosis patients were similar to those in control women. The
pulse amplitude of bioactive LH was significantly higher
(P < 0.01) in women with hyperthecosis compared to
that in normal controls. Hyperinsulinemia induced during LH sampling
resulted in increased bioactive LH levels with no change in
immunoactive LH. These results indicate that 1) women with
hyperthecosis of the ovaries have increased secretion of biologically
active LH, and 2) hyperinsulinemia may enhance the secretion of the
biologically active form of LH.
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Introduction
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HYPERTHECOSIS is a syndrome characterized
by the presence of luteinized thecal cells in the ovarian stroma
associated clinically by masculinization (1). Unlike polycystic ovarian
disease (PCOD), in which luteinized thecal cells are confined to areas
around the cystic atretic follicles, in hyperthecosis large islands of
luteinized thecal cells are scattered all over the stroma away from the
follicles (2). One of the striking biochemical abnormalities in women
with PCOD is inappropriate pulsatile secretion of LH, resulting in
elevated LH levels (3). In vitro studies indicate that LH is
the primary stimulus for androgen production by thecal cells (4).
However, previous reports indicate that women with hyperthecosis of the
ovaries do not have tonic elevation of LH as seen in PCOD (5). Recent
studies show that LH levels and pulse amplitude of immunoactive LH are
inversely related to body mass index (6). All women with hyperthecosis
of the ovaries who have been studied are obese. Their immunoactive LH
levels (LH measured by RIA) have been shown to be low, normal, or only
slightly elevated (7, 8). However, women with hyperthecosis respond to
GnRH analog treatment with a decrease in androgen levels (9).
Therefore, it is possible that women with hyperthecosis have increased
bioactive LH levels. The purpose of our study was to investigate 1) the
secretion of bioactive LH in women with hyperthecosis of the ovaries
and 2) the possible effect of hyperinsulinemia on LH secretion.
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Subjects and Methods
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Six patients with long standing history of hirsutism and
virilization were included in the study. The study was approved by the
institutional review board, and informed consent was obtained from each
patient. The clinical characteristics of these women are shown in Table 1
. All were obese and more than 20%
above their ideal body weight. All had signs of virilization, with
masculine body habitus, temporal balding, and/or clitoral enlargement.
Diagnosis of hyperthecosis was subsequently confirmed in all patients
by histological examination of the ovaries. Three of these patients
were undergoing hysterectomy and oophorectomy, one for severe hirsutism
and virilization who was not interested in future fertility (40 yr old)
and two for endometrial cancer. Three patients had wedge biopsy of the
ovaries to rule out virilizing ovarian tumor, as testosterone levels
were in tumor range. Six nonhirsute women with normal ovulatory cycles
who were obese (>20% ideal body weight) were included as controls.
They were studied in the midproliferative phase of the cycle on day
7.
Endocrine studies in the hyperthecosis and control patients are shown
in Table 2. Testosterone levels were
markedly increased in women with hyperthecosis compared to those in
normal controls and were in tumor range (>200 ng/dL) in most of these
women. Androstenedione levels were also increased.
Dehydroepiandrosterone sulfate levels were normal. FSH and LH levels
were in the normal range.
All women were admitted to the Clinical Research Center after having
consumed a high carbohydrate (300 g) diet for 3 days. On day 1, blood
samples were obtained every 15 min for 6 h. Serum was separated
immediately, and 0.1 mL serum from each sample was collected in a tube
marked pool. All samples were stored at -70 C until the assay. On the
next day, a standard oral glucose tolerance test was performed with
insulin levels. Blood samples for glucose and insulin determinations
were obtained before oral glucose administration and every hour for
3 h thereafter.
To investigate the effect of insulin on LH secretion, hyperinsulinemia
was induced during the 15-min sampling by giving 75 g oral glucose
to two of the hyperthecosis patients and two of the normal controls who
consented for repeat testing.
Hormone assays
All samples, which were obtained at 15-min intervals, were
assayed for bioactive and immunoactive LH. Immunoactive LH was measured
by double antibody RIA with materials provided by the National
Pituitary Agency of the NIH. Bioactive LH was measured by the method of
Dufau et al. (10) as described previously (11). In this
assay we used dispersed rat testis interstitial cells. This in
vitro bioassay is based on production of testosterone by rat
interstitial cells in response to stimulation by LH. LER 907 was used
as a standard for both bioactive and immunoactive LH assays. All LH
measurements were converted to milliinternational units per mL with
reference to the Second International Reference Preparation of human
menopausal gonadotropin. The biopotency of LER 907, in terms of the
Second International Reference Preparation, was 99 IU LH/mg (1 mIU
human menopausal gonadotropin was equivalent to 10 ng LER 907) in the
rat testis interstitial cell assay. The immunopotency of LER 907 is 277
IU LH/mg and 53 IU FSH/mg in terms of the Second International
Reference Preparation of human menopausal gonadotropin. Intra- and
interassay coefficients of variation were 4% and 9.5%, respectively,
for immunoactive LH assay. The intra- and interassay coefficients of
variation for bioactive LH assay were 5.4% and 12.1%, respectively.
All samples from each patient were assayed in a single assay to
eliminate interassay variation.
Insulin levels were measured in duplicate by double antibody RIA as
previously described (12). Plasma glucose was determined by the glucose
oxidase method. Dehydroepiandrosterone sulfate was measured by direct
RIA (13). All other steroids were measured by specific RIA after
fractionation by Celite microcolumn chromatography as previously
described (14). Recoveries ranged from 75–90%. All of the steroid
assays had intraassay coefficients of variation between 4–8% and
interassay coefficients of variation between 6–10%.
Pulse analysis
Pulse analysis of LH secretion was performed by the PC Pulsar
Program, which is a modification of the IBM PC Pulsar Pulse Analysis
Program of Merriam and Wachter (NICHHD, NIH, Bethesda, MD) (15, 16).
The program identifies secretory peaks by height and duration, with the
assay SD used as a scale factor. The cut-off parameters for
G1 to G5 were set at 3.8, 2.6, 1.9, 1.5, and 1.2 times the intraassay
SD and were used as criteria for accepting peaks one, two,
three, four, and five points wide, respectively. The smoothing time, a
window used to calculate the moving average, was set at 360 min. If the
immunoactive and bioactive LH peaks occurred in the same or successive
samples, the peaks were considered concordant.
Statistical analysis
Student’s t test was used for comparing levels
between hyperthecosis and control patients. The relationships between
the measured variables were assessed by linear regression analysis and
Pearson correlation coefficients. All statistical analyses were
performed using the EPISTAT statistical software program (Epistat
Services, Richardson, TX). Differences were considered
significant at P < 0.05.
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Results
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Results of oral glucose tolerance tests revealed the presence of
severe insulin resistance in women with hyperthecosis (Table 3). The mean fasting insulin level in
women with hyperthecosis [42 ± 5 µU (±SD)/mL]
was significantly higher (P < 0.001) than that in
control women (9 ± 2 µU/mL). The insulin response, which is the
sum of insulin concentrations at 1, 2, and 3 h after glucose
administation, was markedly increased (738 ± 235 µU/mL;
P < 0.02) in hyperthecosis patients compared to normal
controls (87 ± 8 µU/mL). The glucose response was higher, but
not significantly different from the control value.
Mean LH levels
Patients with hyperthecosis had significantly higher
(P < 0.002) bioactive LH levels (66.9 ± 13 IU/L)
than controls (29.3 ± 6 IU/L; Table 4). The mean immunoactive LH level in
hyperthecosis patients (11.6 ± 4 IU/mL) was not significantly
different from that in control women (12 ± 2 IU/mL). A
significantly higher mean bioactive/immunoactive LH ratio
(P < 0.001) was observed in women with hyperthecosis
(6.2 ± 0.9 IU/mL) than in normal women (2.4 ± 0.5 IU/mL).
There was a significant (P < 0.01) positive
correlation (r = 0.85) between fasting insulin levels and the
bio/immuno ratio of LH in women with hyperthecosis. There was also a
significant (P < 0.03) positive correlation (r =
0.73) between the sum of the insulin response and the bio/immuno ratio
of LH (Fig. 1). The correlation between
insulin levels and bioactive LH was not statistically significant.
There was no significant correlation between estradiol, estrone, or
testosterone levels and bioactive LH or the bio/immuno ratio of LH.
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Figure 1. Correlation of bio/immuno ratios of LH to
fasting insulin levels (top) and the sum of insulin
responses (bottom).
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Pulse analysis
The results of pulse analysis are shown in Table 4
. The pulse
amplitude of bioactive LH was significantly higher (P
< 0.01) in women with hyperthecosis compared to that in control women.
The interpulse interval for bioactive LH was shorter in women with
hyperthecosis, indicating some increase in the pulse frequency of
bioactive LH. However, the difference was not statistically
significant. Neither pulse amplitude nor pulse frequency of
immunoactive LH in women with hyperthecosis was significantly different
from those in control women. Pulsatile bioactive/immuno active LH
secretion and the bio/immuno ratios of LH in a patient with ovarian
hyperthecosis are shown in Fig. 2. All of
the immunoactive LH pulses are concordant with bioactive LH pulses.
However, some of the bioactive pulses are not associated with an
increase in immunoactive LH. It is possible that the increase in
immunoactive LH during these pulses were not large enough to be
detected as a pulse.
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Figure 2. Pulsatile secretion of bioactive and
immunoactive LH and bio/immuno ratios of LH in a patient with
hyperthecosis of the ovaries. Asterisks indicate LH
pulses.
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In two of the patients in whom hyperinsulinemia was induced during the
15-min sampling, the increase in insulin was followed by an increase in
bioactive LH, with no change in immunoactive LH. This resulted in a
marked increase in the bio/immuno ratio (Fig. 3). Glucose administration in normal
cycling women, in whom the insulin response was normal, did not result
in any change in immunoactive or bioactive LH (Fig. 4).
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Figure 3. Effect of marked hyperinsulinemia on LH
secretion in two hyperthecosis patients. Note the increase in bioactive
LH with no change in immunoactive LH levels. Asterisks
indicate LH pulses. Inset, Glucose and insulin responses
to 75 g oral glucose.
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Figure 4. Effect of physiological increase in insulin
levels on LH secretion in a control patient. No changes were noted in
bioactive or immunoactive LH levels. Asterisks indicate
LH pulses. Inset, Glucose and insulin responses to
75 g oral glucose.
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Discussion
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The cause of extensive luteinization of the ovarian stroma in
hyperthecosis of the ovaries is not known. In vitro studies
indicate that thecal interstitial cells, when exposed to LH, undergo a
dramatic morphological change and develop intracellular organelles
typical of those seen in active steroid-synthesizing cells (4). One of
the effects of LH on ovarian stromal cells could be to induce
luteinization and convert them into steroidogenically active luteinized
stromal cells. Indeed, extensive luteinization of the ovarian stroma
has been observed to occur in patients with trophoblastic tumors
secreting hCG (17). Luteinization of ovarian stroma has also been
observed during pregnancy (18, 19). Therefore, an increase in LH levels
could lead to an increase in luteinization of the ovarian stroma,
resulting in hyperthecosis of the ovaries. In all previous studies in
women with ovarian hyperthecosis, only immunoactive LH levels were
measured, and they were normal (5, 7, 8). The results of our present
study indicate for the first time that these women have increased
bioactive levels even though immunoactive LH levels are normal.
The LH molecule is known to be heterogeneous, and different forms of LH
are secreted by the pituitary (20, 21). Peckham et al.
observed that the molecular size of LH is larger in ovariectomized
monkeys than in intact monkeys, and sialylation of the LH molecule may
determine its bioactivity (22). It is possible that sex steroids and
other hormones could have an effect on the pituitary and alter the
molecular form of LH that is secreted, resulting in an increase or
decrease in the bioactivity. Estrogen treatment in castrated monkeys
altered the molecular size of the pituitary gonadotropins (22).
Electrofocusing studies of pituitary gonadotropins indicate that LH
recovered in the pH range of 7–9.5 have significantly more bioactivity
than LH recovered in the acidic pH range (21). Ding et al.
observed that there is a preponderance of basic isoforms of LH in the
serum of women with PCOD, resulting in an increase in the bio/immuno
ratio (23). As women with hyperthecosis of the ovaries have an increase
in bioactive LH with no increase in immunoactive LH, it indicates that
these women secrete a biologically active form of LH. As we found a
positive correlation between insulin levels and the bio/immuno ratio of
LH in women with hyperthecosis of the ovaries, it is possible that
hyperinsulinemia has an effect on the pituitary and alters the
molecular type of LH that is being secreted. This is further confirmed
by the fact that hyperinsulinemia induced by glucose administration
resulted in an increase in bioactive LH levels in women with
hyperthecosis, with no change in immunoactive LH levels. We did not
observe this effect in normal women. Insulin appears to have this
effect only when present in supraphysiological concentrations, as in
women with hyperthecosis of the ovaries.
Even though there have been numerous studies on inappropriate LH
secretion in PCOD, pulsatile LH secretion in hyperthecosis of the
ovaries has not been studied. The interpulse interval and pulse
amplitude of immunoactive LH secretion in our control women are similar
to those previously reported in the midfollicular phase of the normal
menstrual cycle (24). All previous reports on pulsatile LH secretion in
PCOD indicate an increase in the pulse amplitude of immunoactive LH
(25, 26, 27). However, the results for LH pulse frequency in PCOD have been
controversial. Burger et al. (25) reported an increase in
the pulse frequency of LH secretion in PCOD compared to normal
controls, whereas other investigators observed no increase in pulse
frequency (26, 27, 28). We observed no increase in either pulse frequency
or pulse amplitude of immunoactive LH in women with hyperthecosis of
the ovaries. The pulse frequency and pulse amplitude of bioactive LH
secretion in our control patients are similar to that reported by
Veldhuis et al. in the follicular phase of the menstrual
cycle (29). We are not aware of any previous studies on pulsatile
bioactive LH secretion in PCOD or hyperthecosis of the ovaries.
An increase in bioactive LH with no significant increase in
immunoactive LH indicates that the effect of insulin is probably at the
level of the pituitary rather than the hypothalamus. Specific insulin
receptors have been shown to be present in both the hypothalamus and
the pituitary (30). Adashi et al. investigated the effect of
insulin on the basal and GnRH-stimulated release of gonadotropins in
cultured rat anterior pituitary cells. Insulin was found to enhance
both basal and GnRH-stimulated LH release (31). Dunaif et
al. observed a significant decrease in LH levels in women with
PCOD when circulating insulin levels were lowered with
troglitazone therapy (32).
Previous in vitro studies indicate that insulin stimulates
ovarian stromal and thecal androgen synthesis (33). The results of our
present study suggest that in women with ovarian hyperthecosis,
hyperinsulinemia may also have an effect on the pituitary and increase
the secretion of the biologically active form of LH. Insulin-lowering
drugs, such as troglitazone and metformin, may be the
ideal therapy for patients with hyperthecosis of the ovaries.
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Footnotes
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1 This work was supported by NIH Grants R01-CA-45181 and
M01-RR-0073. 
Received November 4, 1998.
Revised January 12, 1999.
Accepted February 11, 1999.
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Top
Abstract
Introduction
