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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 5 2367-2375
Copyright © 2002 by The Endocrine Society

Other Original Articles

Cosecretion of Estrogen and Inhibin B by a Feminizing Adrenocortical Adenoma: Impact on Gonadotropin Secretion

Jean Marc Kuhn, Hervé Lefebvre, Celine Duparc, Anne Pellerin, Jean Pierre Luton and Georges Strauch

European Institute for Peptide Research, Department of Endocrinology, INSERM, U-413, University Hospital Rouen (J.M.K., H.L., C.D.), 76031 Rouen, France; Department of Endocrinology, Hopital Cochin (J.P.L., G.S.), 75014 Paris, France; and Laboratory of Anatomopathology, University Hospital Rouen (A.P.), 76031 Rouen, France

Address all correspondence and requests for reprints to: Prof. Jean Marc Kuhn, European Institute for Peptide Research 23, Department of Endocrinology, INSERM, U-413, Hôpital Boisguillaume, University Hospital Rouen, 76031 Rouen Cedex, France. E-mail: . jean-marc.kuhn{at}chu-rouen.fr

Abstract

We describe the first reported case of a feminizing adrenocortical adenoma cosecreting estrogens and inhibin B. A 39-yr-old man, with no previous history of disease and free of treatment, complained of gynecomastia without any clinical abnormality. Plasma E2 and T were 496 pmol/liter and 8.7 nmol/liter, respectively. Testicular echography was normal, and abdominal computed tomography scan showed a 28-mm right adrenal tumor. hCG (5000 IU, im) induced a rise in plasma T levels (20.7 nmol/liter) without any change in plasma E2 levels. Basal plasma LH and FSH levels were undetectable. GnRH (100 µg, iv) induced an increase in plasma LH levels without a change in plasma FSH levels. The mean plasma inhibin B level was 330 ± 45 pg/ml (normal range, 94–327). Pulsatile GnRH administration (20 µg/pulse every 90 min for 3 d) stimulated LH secretion, whereas FSH secretion remained blunted. The patient underwent surgery to remove a 12-g adrenal adenoma. Six months later, plasma E2 and T levels were normalized. LH showed a spontaneous pulsatile pattern, and the mean plasma FSH level was 4.8 U/liter. The secretion of both gonadotropins was stimulated during a pulsatile GnRH administration performed in the same manner as before surgery. The mean plasma inhibin B level was 210 ± 25 pg/ml. Immunohistochemical studies revealed the presence of aromatase in clusters of tumor cells. Incubation of tumor sections with anti-ßB-inhibin antibody revealed intense staining in groups of cells that were also labeled with anti-{alpha}-inhibin antibody. These data show that the tumor cosecreted E2 and inhibin B, which were both responsible for inhibition of gonadotropin secretion. Tumor secretions appeared to be much more potent in suppressing FSH than LH levels.

MOST OF THE pure feminizing tumors found in adult men (i.e. Leydig cell tumors and rare adrenal feminizing tumors) are associated with a typical hormonal pattern, including 1) increased plasma levels of estrogens [17ß-E2 and/or estrone (E1)], 2) low plasma gonadotropin levels, and 3) a more or less marked reduction in plasma T levels (1, 2, 3, 4). These hormonal patterns reflect the E2-induced inhibition of gonadotropin secretion, as previously shown under physiological (5) and pathological conditions (6). The concomitant decrease in both plasma LH and FSH levels is consistent with a hypothalamic site of E2 inhibitory feedback. This mechanism has been observed in feminizing adrenal tumors (2) and has been recently demonstrated to be physiologically present in normal men (7). However, in feminizing tumors, FSH appeared more frequently and more strongly suppressed than LH (3, 6), suggesting that tumor secretion could also directly inhibit pituitary FSH synthesis and/or secretion. In agreement with this hypothesis, it has been shown that E2, in addition to its hypothalamic action, is able to reduce FSH secretion through a direct effect on gonadotrophs (4, 8).

Adrenal and testicular tumors have been demonstrated to be able to synthesize inhibin subunits. Rodent tumor Leydig cell lines express inhibin {alpha}- and ßB-subunit genes (9) and secrete bioactive inhibin (10). In humans, immunohistochemical studies showed the presence of inhibin subunits in tumors of the testis and adrenal glands. Inhibin {alpha}-subunit has been demonstrated in tumors of the testis, including Sertoli cell tumors (11, 12) and Leydig cell tumors (12). Inhibin {alpha} immunoreactivity was found to be elevated in plasma of men with feminizing Leydig cell tumors (6), and an increase in plasma inhibin B levels was observed in a case of Sertoli cell tumor in a prepubertal boy with Peutz-Jeghers syndrome (13). Immunohistochemical studies also demonstrated that normal and tumoral human adrenocortical glands were able to synthesize {alpha}- and ß-subunits of inhibin (14, 15, 16, 17). Secretion of inhibin-like immunoreactivity has been observed both in vitro (18) and in vivo (19) from normal adrenal gland and adrenocortical tumors. Androgen and cortisol-secreting adrenal tumors have been reported to be more directly involved (15, 16, 17, 19). An immunohistochemical approach showed the presence of inhibin ßB-subunit in benign, but not malignant, pheochromocytomas (20).

It was thus conceivable that the suppressive effect of feminizing adrenal tumor secretion on gonadotropins may be the result of the subsequent hypothalamic E2 action and both E2 and inhibin B effects on gonadotrophs. This study reports the first known observation of an adrenal adenoma cosecreting E2 and inhibin B. Tumoral secretion was responsible for a marked inhibition of gonadotropic function. In particular, FSH secretion was totally blunted in both basal and GnRH-stimulated conditions.

Case Report

A 39-yr-old man was referred for the evaluation of a bilateral gynecomastia associated with reduced libido. There was no previous history of alcohol abuse or exposure to any treatment. Physiological examination revealed symmetric gynecomastia. Patient height and weight were 168 cm and 71 kg, respectively. The patient had a complete male body contour and a testicular volume of 25 ml. Blood pressure was 130/80 mm Hg. Routine biology, including a liver function test, was normal, and thyroid function showed no abnormality. Testicular echography was normal. A computerized axial tomography scan of the abdomen revealed a right adrenal mass of 28 mm in diameter. The diagnosis of feminizing adrenal tumor was made based on elevated plasma E1 and E2 levels. After detailed endocrine testing and gonadotropin pulsatility studies, the patient underwent a right adrenalectomy. An adrenocortical adenoma weighting 12 g was removed without complications. Pathological examination confirmed a spongiocytic adenoma with an oncocytic appearance. After tumor removal, plasma estrogen levels fell dramatically to normal levels. Six months after surgery the gynecomastia had disappeared, and sexual behavior was normal. An endocrine evaluation similar to the initial testing was then performed. Ten years after surgery, the follow-up examination was normal as well as plasma estrogen levels. Computed tomography scan of the abdomen and chest x-ray were also normal.

Materials and Methods

In vivo studies

The patient gave his informed consent for all endocrine testing. Initial hormonal evaluation used basal measurements and dynamic endocrine tests, including gonadotropin responses to an acute iv administration of 100 µg GnRH, T and E2 changes after an im injection of 5000 IU hCG, and plasma cortisol level after dexamethasone (2 mg/d for 2 d).

Pulsatile LH secretion was assessed before and 6 months after surgery. At both times, pulsatility was studied under basal conditions and after 3 d of a pulsatile GnRH iv administration, by use of a programmable pump (Zyklomat pulse, Ferring Pharmaceuticals Ltd., Kiel, Germany) infusing 20 µg GnRH/pulse every 90 min for 3 d. Blood samples were obtained every 15 min for 8 h.

Plasma hormone levels were measured in duplicate. The following commercial kits were used: respective Immunotech assays (Beckman Coulter, Inc., Villepinte, France) for aldosterone, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, {Delta}4-androstenedione ({Delta}4), and T; respective Immulite 2000 (Diagnostic Products, Los Angeles, CA) for cortisol and E2; RIA for E1 (Biomérieux, Lyon, France); and RIA for 11-deoxycortisol (Cerba, Cergy-Pontoise, France). Gonadotropin measurements used the LH or FSH Immulite assay (Diagnostic Products). Plasma inhibin B levels were measured with a solid phase sandwich ELISA (inhibin B dimer assay, Serotec, Kidlington, UK) on plasma samples obtained during pre- and postoperative pulsatility studies performed without GnRH administration. Plasma samples were stored at -80 C until assay to prevent storage artifact. To avoid interassay variations, all measurements of plasma inhibin levels were made during the same assay run. Using this inhibin B assay, plasma inhibin B levels, determined in 84 proven fathers, ranged between 94–327 pg/ml (21).

Immunohistochemistry

Immunohistochemistry studies were performed on material fixed in formalin and embedded in paraffin wax. Before staining, deparaffinized sections were incubated for 60 min at room temperature, with one of the following antibodies: 1) a rabbit polyclonal antibody directed against human placental aromatase (1:1500), provided by Dr. Osawa (Hauptman-Woodward Medical Research Institute, Buffalo, NY); 2) a goat polyclonal antibody to human inhibin {alpha}-subunit (1:250; Santa Cruz Biotechnology, Inc., Santa Cruz, CA); and 3) a goat polyclonal antibody to human inhibin ßB-subunit (1:50; Santa Cruz Biotechnology, Inc.). Aromatase immunoreactivity was revealed using a labeled streptavidin-biotin kit (LSAB, DAKO Corp., Ely, UK). Peroxidase was visualized with a diaminobenzidine solution (DAKO Corp.). Sections were counterstained with Mayer’s hematoxylin solution, dehydrated, mounted in xylene, and examined with a light microscope (Olympus Corp., Tokyo, Japan). Inhibin {alpha} and ßB immunoreactivities were visualized by incubating the sections with a fluorescein isothiocyanate (FITC)-conjugated swine antigoat {gamma}-globulin (SAG) diluted 1:100. For double staining, sections were incubated with either anti-{alpha} or anti-ßB inhibin subunit antibodies revealed with a Texas Red-conjugated donkey antigoat {gamma}-globulin (diluted 1:100) and FITC-SAG (diluted 1:100), respectively. The preparations were examined on a Leitz Orthoplan microscope equipped with a Vario Orthomat system (Rockleigh, NJ). For control experiments, antibodies were preabsorbed with either inhibin {alpha}- or ßB-subunit (Santa Cruz Biotechnology, Inc.) at 8 mg/liter.

Results

In vivo studies

Basal plasma hormone levels measured before and after surgery are shown in Table 1Go. Before removal of the tumor, plasma E1 and E2 levels were, respectively, 9 and 4 times higher than those in normal adult men. Plasma T was low, whereas plasma {Delta}4 was increased, and dehydroepiandrosterone sulfate was in the normal range. Plasma 17- hydroxyprogesterone levels were normal, and plasma 11-deoxycortisol was increased. Plasma cortisol levels were normal and followed a normal nycthemeral pattern. Urinary free cortisol excretion was 170 nmol/24 h (normal range, 50–220). Plasma cortisol dropped to less than 25 nmol/liter during a dexamethasone suppression test. Plasma aldosterone levels were in the normal range in both the upright and supine positions. Plasma steroid levels measured during the gonadotropin pulsatility studies, either before or after removal of the tumor, are shown in Table 2Go. Briefly, mean plasma E2, which was elevated before surgery, did not change during pulsatile administration of GnRH. In contrast, plasma T levels increased 3 times over basal levels in response to this treatment. Tumor removal was followed by a normalization in plasma E2 and T levels, which both rose during the pulsatile administration of GnRH. Three days after the injection of hCG, T levels reached 19 nmol/liter, whereas plasma E2 did not change from the baseline value (Fig. 1Go). These patterns of response to hCG were clearly different from those observed in normal men in whom plasma T and E2 rose to 47.5 ± 5.5 nmol/liter and 420 ± 40 pmol/liter, respectively (3).


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  		Table 1. Basal plasma steroid hormone levels before and 6 months after surgery

 

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  		Table 2. Mean (±SEM) plasma T and 17ß-E2 levels measured at least four times during each polsatility study

 


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  		Figure 1. hCG-induced changes in plasma T and 17ß-E2 levels in the patient before surgery. Response patterns of normal men (mean ± SEM) are shown for comparison (3 ).

 
Before surgery, basal plasma LH and FSH levels were undetectable (<1 and <0.5 U/liter respectively). Acute GnRH administration (100 µg iv) induced a lower rise in plasma LH levels than in normal men, whereas plasma FSH levels remained undetectable (Fig. 2Go). Pulsatile GnRH administration restored LH (Fig. 3Go), but failed to stimulate FSH secretion (Fig. 4Go). Six months after surgery, a spontaneously pulsatile LH pattern was restored. The plasma LH pulse pattern was increased in both amplitude and frequency by pulsatile administration of GnRH (Fig. 3Go). Plasma FSH levels significantly rose after tumor removal and were increased by the pulsatile administration of GnRH (Fig. 4Go).



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  		Figure 2. Changes in plasma LH and FSH levels after acute iv injection of 100 µg GnRH before surgery. Response patterns of normal men (mean ± SEM) are shown for comparison (3 ).

 


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  		Figure 3. LH pulsatile patterns measured before and 6 months after surgery either spontaneously or during the pulsatile administration of GnRH (20 µg/pulse, iv, every 90 min for 3 d).

 


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  		Figure 4. Mean (±SEM) plasma FSH levels measured during LH pulsatility studies. BS, Before surgery either with (BS + GnRH; 20 µg/pulse, iv, every 90 min for 3 d) or without GnRH administration; AS, after surgery either with (AS + GnRH) or without GnRH administration. *, P < 0.01; **, P < 0.001 (vs. BS).

 
Mean (±SEM) plasma inhibin B levels, measured on plasma samples obtained during pulsatility studies performed without GnRH administration, were 330 ± 45 pg/ml before and 210 ± 25 pg/ml after tumor removal (Fig. 5Go).



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  		Figure 5. Plasma inhibin B levels in samples drawn for the LH pulsatility studies, performed without GnRH treatment, before and 6 months after surgical removal of the tumor. Shaded area, Normal range of plasma inhibin B levels measured in 84 proven fathers using the inhibin B dimer assay (Serotec; from Ref. 21 ).

 
Immunohistochemistry

Labeling of adrenocortical adenoma sections with antiaromatase antibodies revealed the presence of immunoreactive cell clusters disseminated in the tissue (Fig. 6Go). A similar characteristic was observed after the incubation of tissue sections with either inhibin {alpha}- or ßB-subunit antisera (Fig. 6Go). In addition, inhibin {alpha}- and ßB-subunit-like immunoreactivities were localized in the same cells (Fig. 7GoGoGo).



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  		Figure 6. Immunostaining with the antiaromatase antibody. Particularly illustrative zones are indicated by arrowheads. Scale bar, 30 µm.

 


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  		Figure 7. Photomicrographs of sections of estrogen-secreting adrenal adenoma labeled with different antibodies. A and B, Immunostaining with the antiinhibin {alpha}-subunit antibody without (A) or with (B) preabsorption with inhibin {alpha}-subunit; C and D, immunostaining with the anti-inhibin ßB-subunit antibody without (C) or with (D) preabsorption with inhibin ßB-subunit; E and F, immunostaining with either the anti-inhibin {alpha}-subunit antibody (E) or the antiinhibin ßB-subunit antibody (F) in two consecutive sections of the tumor. Adjacent sections were incubated with a goat antihuman antibody to inhibin {alpha}-subunit revealed with donkey antigoat {gamma}-globulin-Texas Red {gamma}-globulin or with a goat antihuman to inhibin ßB-subunit revealed with SAG-FITC. Scale bars, 60 µm.

 


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  		Figure 7A. Continued.

 


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  		Figure 7B. Continued.

 
Discussion

Feminizing adrenal tumors are rare, as demonstrated by the small number of cases reported in the literature (1, 2, 4, 22). In the present case tumoral secretions as well as their impact on gonadotropic function were investigated using in vivo and immunohistochemical procedures.

Several data indicate that estrogen oversecretion are derived from the adrenal tumor itself. Firstly, E1, which has been shown to be synthesized by normal adrenal glands (23), was the predominant circulating estrogen in our patient. Secondly, the lack of influence of exogenous hCG on plasma E2 levels showed that the source of estrogens was hCG insensitive and probably extragonadal. This observation is consistent with the fact that testicular synthesis of E2 was certainly reduced as a consequence of gonadotropin suppression. Finally, aromatase was detected in tumor cells by immunohistochemistry, indicating that the adrenal adenoma was able to produce estrogens through local aromatization of adrenal androgens. Therefore, the high plasma E2 levels were probably the consequence of the tumoral aromatization of {Delta}4 into E1, followed by peripheral conversion of E1 into E2. This mechanism was suggested by highly elevated plasma {Delta}4 and E1 levels while plasma T levels were low. These data are in agreement with previous findings for a feminizing adrenocortical carcinoma that expressed high levels of aromatase activity (4).

The basal endocrine pattern of this adrenal tumor mimicked the usual hormonal characteristics of feminizing Leydig cell tumors of the testis, i.e. elevated plasma E2 levels, gonadotropin suppression, and decreased plasma T levels. In contrast, hCG administration did not induce the sharp rise in plasma E2 levels (>290 pmol/liter 3 d after hCG injection) observed in men with feminizing Leydig cell tumors (3). In our patient, both hCG injection and pulsatile GnRH infusion were followed by an increase in plasma T levels that probably reflects the response of Leydig cells to the stimulus. In contrast, the pattern of plasma E2 was not significantly influenced by either hCG or pulsatile GnRH administration, suggesting that the adrenal tumor did not express LH receptors.

The role of E2 to negatively retroregulate gonadotropin secretion in man has been clearly demonstrated in several human models, including pathological cases (2, 3, 4, 24, 25) and normal men (5, 7, 26, 27, 28). According to these studies, it can be concluded that high estrogen levels originating from the tumor were responsible for the inhibition of gonadotropin secretion. The site of estrogen action on gonadotropin secretion has been a matter of controversy for a number of years. Most researchers have favored a predominant pituitary gland effect (2, 5, 7, 26, 27, 29). Recently, Hayes et al. (7) demonstrated a hypothalamic site of estrogen feedback on gonadotropin secretion in man, as previously suggested (30, 31). In our case, several results favor a pituitary site of action: decreased gonadotropin response to acute GnRH testing and lower LH plasma levels before, rather than after, surgery during pulsatile GnRH administration. In contrast, the rise in plasma LH during the GnRH test as well as the ability of pulsatile GnRH to stimulate gonadotropin secretion agree with the hypothesis of a hypothalamic effect of estrogens. Therefore, it is likely that estrogens inhibited LH secretion at both hypothalamic and pituitary sites.

In contrast to LH, FSH secretion was totally blunted both in basal conditions and after stimulation with GnRH. This suggests a direct inhibition of FSH synthesis and/or secretion at the pituitary level, and that estrogens, regardless of whether they represent a sole tumoral secretion, were more potent in inhibiting FSH than LH. Therefore, E2 is known to decrease FSH secretion from mammal and human pituitary cultures (32, 33, 34) and to suppress FSHß gene expression in ovine pituitary culture (34, 35, 36). However, these results differ from those observed using in vivo or in vitro models of other mammal species (37, 38). Otherwise, orally given estrogens did not suppress the GnRH-induced response of FSH in male to female transsexuals (39), and E2 did not totally blunt FSHß gene expression (35, 36), suggesting that in the present observation another associated factor secreted by the tumor led to the inhibition of FSH secretion. Inhibin B secretion by the tumor could be considered a possible explanation. Indeed, inhibin has been demonstrated to reduce FSH secretion in castrated male rats (40) and is known to directly retroregulate pituitary FSH secretion (41). Furthermore, Illingworth et al. (42) showed that dimeric inhibin B levels and FSH were negatively correlated in adult men. Otherwise, either normal or tumoral human adrenal glands can synthesize inhibin subunits (14, 15, 16, 17, 18, 19), as do tumors of the testis, including Sertoli cell tumors (11, 13) and feminizing Leydig cell tumors (6, 43). To test this possibility, we measured plasma inhibin B levels in the pulsatility plasma samples obtained before and 6 months after surgery. Before surgery, plasma inhibin B levels were clearly in the upper third of the normal range for adult men. As FSH secretion was completely blunted before removal of the tumor, a decrease in plasma inhibin B levels below normal values should have been observed as in GnRH-deficient men (44, 45) or patients whose gonadotropin secretion is suppressed (46, 47). Another paradoxical finding was the postoperative decrease in plasma inhibin B levels. Indeed, normalization of gonadotropin secretion after surgery was expected to be associated with a rise of plasma inhibin B levels, as observed in GnRH-deficient patients treated with either GnRH or recombinant human gonadotropins (44, 45). These surprising results could only be explained by FSH-independent secretion of inhibin B by the tumor. This hypothesis was confirmed by the immunohistochemical demonstration of the presence of inhibin {alpha}- and ßB-chain in the same tumoral cells. The combination of increased plasma E2 and inhibin B levels could have explained the dramatic suppression of FSH secretion associated with the tumor.

In conclusion, we report the first case of a feminizing adrenal tumor cosecreting E2 and inhibin B. This unusual secretory pattern appeared to be due to a rise of aromatase activity and increased inhibin B synthesis compared with those in the normal adrenal gland. Consequently, gonadotropin secretion was inhibited, with a more pronounced suppression in FSH than in LH secretion. In fact, plasma inhibin B levels could represent a marker of follow-up for feminizing tumors, particularly when the hormonal pattern includes undetectable plasma FSH levels. Finally, with the exception of one biological characteristic (i.e. lack of response to hCG in vivo), this tumor appeared to mimic the hormonal pattern of feminizing Leydig cell tumors of the testis.

Acknowledgments

We thank Dr. A. Vieillefond for providing pathological data, Mrs. D. Guiban and C. Fournier for performing hormone assays, and Mr. R. Medeiros for his advice on editing the manuscript.

Footnotes

Abbreviations: {Delta}4, {Delta}4-Androstenedione; E1, estrone; FITC, fluorescein isothiocyanate; SAG, swine antigoat {gamma}-globulin.

Received May 1, 2001.

Accepted January 22, 2002.

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