Original Article
Recognition of Gonadotroph Adenomas in Women
N Engl J Med 1991; 324:589-594February 28, 1991
- Abstract
Background
Pituitary adenomas that arise from the gonadotroph cells are being recognized with increasing frequency in men, but they are still rarely recognized in women. This rarity could be the result of an actual difference in occurrence or of greater difficulty in recognition. The tumors are usually recognized in men more than 50 years old, but elevated serum gonadotropin levels in women of that age could be produced by normal gonadotroph cells.
Methods
Because the stimulation of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and the beta subunit of LH (LHβ) by thyrotropin-releasing hormone (TRH) is a characteristic of gonadotroph adenomas in men, we administered TRH to 16 women with apparently nonsecreting pituitary macroadenomas and measured serum FSH, LH, LHβ, and the glycoprotein hormone α subunit every 15 minutes for 90 minutes before and 90 minutes after. The results were compared with the responses in 16 healthy women matched for age and in 10 women with macroadenomas secreting prolactin, growth hormone, or corticotropin. The tumors from 12 of the women with nonsecreting adenomas were cultured, and the secretion of FSH, LH, and LHβ in culture was determined.
Results
Eleven of the 16 women with apparently nonsecreting adenomas had significant increases in serum LHβ in response to TRH, 3 had FSH responses, and 4 had LH responses. None of the 16 healthy women and none of the 10 women with secreting macroadenomas had LHβ, FSH, or LH responses to TRH. Ten of the 12 adenomas that were cultured secreted readily detectable amounts of FSH, LH, and LHβ, and their secretion in vitro correlated with the patients' responses to TRH in vivo.
Conclusions
Most apparently nonsecreting pituitary macroadenomas in women arise from gonadotroph cells. The majority of these can be recognized, even in postmenopausal women, by the serum LHβ responses to TRH, and some can be recognized by the responses of serum FSH and LH. (N Engl J Med 1991; 324:589–94.)
Media in This Article
Figure 1
Responses of Serum FSH, LH, LHβ, and α Subunit to the Intravenous Administration of 400 μg of TRH in 16 Women with Nonsecreting Pituitary Adenomas.Table 1
Basal Serum FSH, LH, and α-Subunit Concentrations in 16 Women with Nonsecreting Pituitary Macroadenomas.*Article Activity
- Article
A DENOMAS that arise from the gonadotroph cells of the pituitary gland account for a substantial percentage of pituitary macroadenomas in men, but they are rarely recognized in women. When gonadotroph adenomas were first described in men less than 20 years ago,1 2 3 4 5 they were thought to be rare, but recent studies of basal concentrations of gonadotropins and their subunits demonstrate that such tumors probably account for 20 to 25 percent of all pituitary macroadenomas in men.6 , 7 Few women, however, have been reported to have clinically recognizable gonadotroph adenomas.8 , 9
The rarity with which gonadotroph adenomas have been reported in women could be the consequence of a greater difficulty in recognizing these adenomas in women than in men. Gonadotroph adenomas are usually recognized in men who are more than 50 years old.6 In a woman of that age who has a pituitary adenoma and elevated serum concentrations of gonadotropins and their subunits, recognizing that the tumor is a gonadotroph adenoma is difficult; it could also be another kind of pituitary adenoma in a patient whose increased gonadotropin secretion originates in normal gonadotroph cells. Studies of pituitary adenomas in vitro, however, suggest that gonadotroph adenomas occur much more commonly than recognized. When pituitary adenomas that are thought to be nonsecreting, as judged by basal serum concentrations of pituitary hormones, are studied in vitro — whether by measurements of hormonal secretion from cultured adenoma cells, 10 11 12 immunospecific staining for pituitary hormones,10 , 11 , 13 or tests for the presence of the messenger RNAs for the hormones14 — at least two thirds of them contain or secrete the products of gonadotroph cells. This in vitro evidence that such adenomas arise from gonadotroph cells has come from tumors from women as often as tumors from men, 10 , 12 13 14 which suggests that gonadotroph adenomas do occur in women, but that they are not recognized before surgical excision.
The goal of our study was to determine whether one of the characteristics of gonadotroph adenomas that has been recognized in studies in men — the secretion of gonadotropins and their subunits in response to thyrotropin-releasing hormone (TRH)15 , 16 — could be used to recognize such adenomas in women in vivo. To this end, we determined the responses of gonadotropins and their subunits to TRH in 16 consecutive women with nonsecreting adenomas, and we compared these responses with those in 16 healthy women matched for age and in 10 women with hormonesecreting adenomas. We also compared the serum hormonal and subunit responses to TRH with the secretion of these substances by the excised adenoma tissue in dispersed cell culture, to determine how many of the gonadotroph adenomas identified by secretion in culture had been recognized as such by their responses to TRH in vivo.
Methods
Selection of Subjects
Women who presented to the endocrinology service of the Hospital of the University of Pennsylvania for a newly suspected pituitary adenoma were evaluated for pituitary hormonal hypersecretion by measurements of serum prolactin, insulin-like growth factor I (IGF-I), thyroxine, and thyroid-stimulating hormone. They also gave informed consent in writing to the protocol described below. Subsequently, those who met the following criteria were given a diagnosis of nonsecreting pituitary macroadenoma: an intrasellarmass lesion more than 1 cm in its longest dimension as seen on magnetic resonance imaging; histologic confirmation of a pituitary adenoma in surgically excised tissue; and lack of evidence that the adenoma had arisen from lactotroph cells (serum prolactin concentration < 100 μg per liter), somatotroph cells (no clinical manifestations of acromegaly and serum IGF-I <2.2×l0×10×10 3 U per liter), or corticotroph cells (no clinical manifestations of Cushing's syndrome). Sixteen women, whose mean age was 58 years (range, 25 to 78), met these criteria.
In the course of selecting the women with nonsecreting adenomas, we found 10 women who had secreting pituitary macroadenomas according to the following criteria: an intrasellar-mass lesion more than 1 cm in its longest dimension as seen on magnetic resonance imaging; evidence that the mass was a pituitary adenoma that had arisen from lactotroph cells (serum prolactin concentration ≥100 μg per liter), somatotroph cells (manifestations of acromegaly, serum growth hormone concentration >2 μg per liter after an oral glucose load, and serum IGF-I concentration ≥2.2×10×10×10 3 U per liter), or corticotroph cells (cushingoid features and basal 24-hour urinary excretion of cortisol >552 nmol [200 μg], not normally suppressible after treatment with 2 mg of dexamethasone per day for two days, but suppressible after treatment with 8 mg per day for two days). These women also gave informed consent. Their mean age was 45 years (range, 31 to 57).
Sixteen women were chosen as healthy, age-matched control subjects for the patients with nonsecreting adenomas, and they too gave informed consent. Because 14 of the 16 patients with nonsecreting adenomas were more than 48 years old, only postmenopausal women were selected for the age-matched control group. The mean age of these women was 64 years (range, 52 to 79). None of the women had an ovariectomy, and none were taking an estrogen or other medication thought to affect pituitary—ovarian function. Twelve premenopausal women were chosen as a second control group. Their mean age was 29 years (range, 22 to 40).
TRH Protocol
Each patient and each healthy age-matched subject participated in the following protocol, which had been approved by the University of Pennsylvania Committee on Studies Involving Humans. Blood was sampled every 15 minutes for 90 minutes before and 90 minutes after the intravenous administration of 400 μg of TRH, and the serum was stored at — 20°C for subsequent assay of follicle-stimulating hormone (FSH), luteinizing hormone (LH), the glycoprotein hormone α subunit, and the beta subunit of LH (LHβ). The healthy premenopausal women had blood sampled three times in one hour on one day during the mid-follicular phase (days 8 to 10) of the menstrual cycle.
Cell Culture
Sufficient tissue was obtained at the time of transsphenoidal excision of the adenoma in 12 of the 16 patients to establish the tissue in dispersed cell culture. The cell-culture technique, which has been previously described,17 involved mincing the tissue, digesting it with 0.1 percent trypsin and 0.01 percent DNase, and incubating 0.5 × 10×10×10×10×10×10 6 cells in each of two to six 16-mm polylysine-coated wells with 45 percent Dulbecco's modified Eagle's medium, 45 percent F12, and 10 percent fetal-calf serum at 37°C. The medium was changed every three to four days and stored at — 20°C until assayed for FSH, LH, and LHβ.
Assays
We measured serum LH by a double monoclonal, two-site immunoradiometric assay using reagents obtained from ICN Biomedicals (Costa Mesa, Calif.). The cross-reactivities of LHβ and the glycoprotein hormone α subunit in this assay were less than 0.05 percent and less than 0.2 percent, respectively. The lower limit of sensitivity was 0.9 IU per liter in terms of the second international reference preparation of human menopausal gonadotropin and 47 ng per liter in terms of human LH reference preparation 12. The interassay and intraassay coefficients of variation were both less than 8 percent. Serum FSH, LHβ, and α subunit were measured by polyclonal assays, as previously described.18 The lower limits of sensitivity of these assays were 1.0 IU per liter (263 ng per liter in terms of human FSH reference preparation I3), 20 ng per liter, and 100 ng per liter, respectively. The cross-reactivity of LH in the LHβ assay was 6.1 percent; in the α-subunit assay, that of LH was 9.4 percent, and that of FSH was 7.7 percent.
Statistical Analysis
Because of the large variability in basal values of the hormones and subunits among both patients and healthy subjects, all values for each woman, both before and after the administration of TRH, were expressed as a percentage of the mean basal value, which was defined as the mean of the seven pre-TRH values. The maximal response of each hormone and subunit to TRH was calculated as the mean of the 15-to-45-minute values for LH, LHβ, and α subunit and the mean of the 30to–90-minute values for FSH. The maximal incremental response to TRH for each intact hormone and subunit was calculated as follows: Maximal percent incremental response = (maximal response to TRH — mean basal value) × 100/mean basal value. For the patients, a greater-than-normal response to TRH was defined as more than the mean +2 SD in the healthy age-matched women. The response of each patient's hormones and subunits to TRH was also analyzed by one-way analysis of variance comparing the values before and after the administration of TRH; P values less than 0.05 were considered to indicate significance. The two methods gave similar results, in that each response that was greater than normal was also significantly different from the basal value by analysis of variance.
Results
Basal Serum Hormonal and Subunit Concentrations
The basal serum concentrations of FSH, LH, and α subunit in the 16 patients with nonsecreting pituitary adenomas varied widely (Table 1). Some values were within the range of those in the 16 healthy age-matched (i.e., postmenopausal) women, but others were lower, more typical of those in the healthy premenopausal women or even lower. In most patients the values for the hormones and subunits were roughly appropriate for one another, but there were two notable exceptions. Patient 1 had a serum α-subunit value in the normal postmenopausal range, but serum FSH and LH values far below that range. Patient 12 had a serum FSH value within the normal postmenopausal range, but an LH value far below it. The basal serum concentrations of FSH and LH and α subunit in the 10 patients with secreting adenomas also varied widely, but in each patient the values of the hormones and subunits were appropriate for one another.
The mean (±SE) basal serum estradiol concentrations in each of the groups were as follows: patients with nonsecreting adenomas, 128±29 pmol per liter; those with secreting adenomas, 202±62 pmol per liter; healthy age-matched women, 88±11 pmol per liter; and healthy premenopausal women, 235±37 pmol per liter.
Responses to TRH
After the administration of TRH, none of the healthy postmenopausal women had an increase in serum FSH, LH, α subunit, or LHβ. The ranges of values in these women are shown in Figure 1Figure 1
Responses of Serum FSH, LH, LHβ, and α Subunit to the Intravenous Administration of 400 μg of TRH in 16 Women with Nonsecreting Pituitary Adenomas.. Among the women with nonsecreting adenomas, 3 had significant serum FSH responses to TRH, ranging from 89 to 239 percent above the basal level; 4 had significant LH responses, ranging from 77 to 117 percent; 4 had significant α-subunit responses, ranging from 54 to 1165 percent; and 11 had significant LHβ responses, ranging from 23 to 402 percent (Table 2Table 2
Serum LHβ Concentrations at Base Line and in Response to TRH in 16 Women with Nonsecreting Pituitary Macroadenomas.*). For several reasons, it is unlikely that the LHβ responses represented cross-reactivity of LH in the LHβ assay: the degree of LH cross-reactivity was insufficient to account for the measured LHβ increase; 11 women had LHβ responses, but only 4 of them had LH responses; and in the patients who had both LH and LHβ responses the magnitude of the LHβ response was greater and the time of the peak response was earlier.Among the women with secreting pituitary macroadenomas (adenomas secreting growth hormone, prolactin, or corticotropin), none had an increase in LHβ, FSH, or LH. One woman with a growth hormonesecreting adenoma, however, had a 116 percent increase in the serum α-subunit concentration in response to TRH, which may well have reflected the fact that some pituitary adenomas secrete growth hormone and α subunit concomitantly.
Secretion in Culture
Adenoma tissue was available for dispersed cell culture from 12 of the 16 patients with nonsecreting adenomas. The cultured cells from 10 of the 12 secreted readily detectable amounts of FSH, LH, and LHβ for 7 to 28 days. The values for the first three to four days are shown in Table 3Table 3
Secretion of FSH, LH, and LHβ by Cultured Cells of Pituitary Macroadenomas Excised from 12 Women.*. The secretion in culture correlated roughly with behavior in vivo. The adenomas of Patients 6 and 13 secreted the largest amounts of FSH and LH in vitro, and these patients had substantial hormonal and subunit responses to TRH in vivo. The only two patients whose adenoma cells secreted virtually no FSH, LH, or LHβ in culture (Patients 5 and 11 ) had no hormonal or subunit response in vivo.Discussion
The results presented here demonstrate that in the majority of women with pituitary macroadenomas that are considered nonsecreting according to current criteria, the adenomas are probably of gonadotroph origin. In 11 of the 16 women with nonsecreting adenomas, TRH stimulated a significant increase in the serum concentration of LHβ. In contrast, TRH did not stimulate a significant increase in the serum LHβ concentration in any of 16 healthy age-matched women or in any of 10 women with macroadenomas that were secreting prolactin, growth hormone, or corticotropin. Of the 11 women who had serum LHβ responses to TRH in vivo, the adenomas of 9 were studied in dispersed cell culture. All nine secreted readily detectable amounts of both LH and FSH in culture, supporting the gonadotroph-cell origin of the adenomas.
The response of gonadotropins and their subunits to TRH is an established characteristic of gonadotroph adenomas in men. Men whose pituitary adenomas are recognized to be of gonadotroph-cell origin because of a supranormal serum FSH concentration often have serum FSH and LH responses to TRH, as measured by polyclonal assays.15 , 16 According to the results of gel filtration of serum drawn before and after the administration of TRH, the FSH response appears to be a response of intact FSH, but the LH response is apparently more a response of LHβ than of intact LH.18 When such adenomas are excised and established in dispersed cell culture, they also secrete FSH and LH in response to TRH.16 , 18 In contrast, men with supranormal serum FSH and LH concentrations due to primary hypogonadism do not have responses of either substance to TRH,15 just like the postmenopausal women in our study.
The demonstration that a majority of apparently nonsecreting adenomas in women can be recognized by in vivo criteria to be gonadotroph adenomas is not entirely surprising, however, in view of in vitro data obtained in the past few years. When apparently nonsecreting adenomas are excised and established in dispersed cell culture, 90 to 100 percent secrete some combination of gonadotropins and their subunits.10 11 12 When excised adenomas are studied with immunohistochemical techniques, 50 to 85 percent are found to contain some combination of the beta subunit of FSH, LHβ3, and α subunit.10 , 11 , 13 Messenger RNAs for anterior pituitary peptides have been extracted from such adenomas, and those for the beta subunit of FSH, LHβ, and α subunit were found in 77 percent.14 Although these in vitro data showed that many apparently nonsecreting adenomas were actually gonadotroph adenomas, recognizing them in vivo has remained difficult.
In vivo recognition is difficult in women because, as in men,6 the tumors usually do not become large enough to cause neurologic symptoms and thus to come to medical attention until the patient is over the age of 50. Elevated basal serum gonadotropin concentrations in a woman of that age, assuming she is postmenopausal, could be the result of secretion from a gonadotroph adenoma or from normal gonadotroph cells. In a minority of women with pituitary macroadenomas, certain combinations of gonadotropin and subunit levels can be highly suggestive of the gonadotroph origin of the adenoma: an α-subunit concentration that is inappropriately elevated for the concentrations of FSH and LH, as in our Patient 1, or a markedly elevated FSH concentration in the presence of a subnormal LH concentration, as in Patient 12 and as previously reported.8
The results presented here suggest that gonadotroph adenomas can usually be recognized in vivo in women — even in those who are postmenopausal —by the response of serum LHβ to TRH. Some women with apparently nonsecreting adenomas also have significant FSH or LH responses to TRH, as did three and four of our patients, respectively, and others reported on previously.13 , 21 These responses are diagnostically useful when they occur. Apparently more useful, however, is the LHβ response, which occurred in 11 of the 16 women in our study with apparently nonsecreting macroadenomas, but in none of 16 healthy age-matched women and none of 10 women with secreting macroadenomas.
The demonstration that the majority of apparently nonsecreting macroadenomas in women are actually gonadotroph adenomas and that they can be recognized as such in vivo may be important in several ways. First, recognizing that an intrasellar lesion arises from gonadotroph cells means that it is pituitary and not another kind of intrasellar lesion, a distinction that cannot always be made otherwise, even with the newest imaging procedures. Second, a pretreatment response of serum LHβ to TRH provides a marker by which to follow the effectiveness of whatever therapy is chosen. Third, recognizing the commonplace occurrence of gonadotroph adenomas in women as well as men should give greater impetus to efforts, now just beginning, to develop specific pharmacologic treatment for gonadotroph adenomas.
We conclude from these results that most apparently nonsecreting pituitary macroadenomas in women are actually of gonadotroph origin. The gonadotroph origin can be recognized in vivo in a majority of these women, even after menopause, by a serum LHβ response to TRH, and in a minority by serum FSH and LH responses to TRH.
Supported by a grant (DK-42139) to Dr. Snyder from the National Institutes of Health and a Clinical Research Center grant (RR-40) to the University of Pennsylvania.
We are indebted to Ms. Cordelia Shute and the nurses of the Clinical Research Center of the Hospital of the University of Pennsylvania for caring for the patients, to Ms. Janet Quigley for coordination of patient activities, to Ms. Judith Simms for preparation of the manuscript, and to the National Hormone and Pituitary Program for providing reagents for the FSH, LHβ, and α-subunit assays.
Source Information
From the Endocrinology Section, Department of Medicine (L.D., H.M.B., P.J. Snyder), and the Division of Neurosurgery (T.A.G.), University of Pennsylvania School of Medicine, and the Neuroophthalmology Service, Wills Eye Hospital (P.J. Savino, R.C.S., T.M.B.), both in Philadelphia. Address reprint requests to Dr. Snyder at 611 Clinical Research Bldg., 422 Curie Blvd., Philadelphia, PA 19104–6149.
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