FERTILITY AND STERILITY Copyright © 1978 The American Fertility Society
Vol. 29, No.2, February 1978 Prinred in U.SA.
SEXUAL FUNCTION IN MALES WITH PITUITARY TUMORS
PER OLOV LUNDBERG, M.D.* LEIF WIDE, M.D.t Departments of Neurology and Clinical Chemistry, University Hospital, S-750 14 Uppsala 14, Sweden
The frequency of decreased or absent libido/potency was studied in 65 males with tumors in the region of the sella turcica. The presence or absence of sexual dysfunction was correlated to the serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and prolactin; to the LH response toLH-releasing hormone (LH-RH); and to certain tumor characteristics. Seventy-six per cent of the patients had decreased or absent libido/potency. The corresponding figures for those with an intrasellar tumor and those with a large tumor with extention into the suprasellar region were 54% and 88%, respectively. Only 1 of 20 patients whose first symptom of a tumor was a decrease in libido or potency consulted a doctor because of this symptom. The serum levels of FSH and LH in the group of patients with decreased or absent libido/potency were within the normal range in 47% and 34%, respectively, but almost all of these patients had low serum levels of testosterone. The LH response to LH-RH was better related to the presence or absence of sexual dysfunction than was the basal LH level. There was no significant relationship between decreased or absent libido/potency and increased serum prolactin levels. A low serum testosterone level indicates an endocrine etiology of the sexual dysfunction. When combined with a normal or decreased level of gonadotropins, a primary disturbance of hypothalamic-pituitary function is probable.
It is well known that patients with pituitary tumors may have sexual problems, and the frequency with which these occur is reported to be 35% to 73% .1-6 It is believed that in many of these patients the symptoms of sexual dysfunction are due to a lack of androgen caused by a combined gonadal and adrenal gland insufficiency. However, this problem has previously been studied only superficially, and no real attempts have been made to correlate specific sexual problems directly with particular tumor properties and endocrine findings. The purpose of the present investigation was to study the occurrence and nature of sexual problems in 65 males with a tumor in the region of the sella turcica and to correlate the findings with tumor size and blood hormone levels.
EXPERUMENTALPROCEDURE
Subjects. All 65 patients were adult males, the youngest at the first examination being 18 years old. The oldest patient was 67 years old at the first examination. Four of the patients had not had a normal puberty and six of them had not undergone normal psychosexual development. The others had had a normal puberty and had had a normal adult sex life for some years. The patients were studied before and after surgery and/or radiotherapy if such procedures were performed. Twenty-nine of the patients had pituitary adenomas which extended into the intra- and suprasellar regions. Twenty-three patients had purely intrasellar tumors, and eleven of these had clinical signs of acromegaly. In four additional patients there was total destruction of the sellar region of the type seen in diffuse invasive adenomas. 7 Seven patients had craniopharyngiomas, one patient had a menil'lgioma, and one
Received August 24,1977; accepted September 12, 1977. *Professor and Head, Department of Neurology To whom reprint requests should be addressed. t Assistant Professor, Department of Clinical Chemistry.
175
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LUNDBERG AND WIDE
patient had an aspergilloma; the tumors of the latter two patients extended into the sella turcica. Clinical hypoandrogenism (such as loss of beard and pubic hair, testicular atrophy, atrophy of the prostate gland, azoospermia, or even total aspermia) was found in most cases. Tumor size and localization were defined by results of skull x-ray, pneumoencephalography, and visual field studies. According to these results the patients were separated into two groups. One group comprised 23 males with purely intrasellar tumors and the other group included 42 males with larger tumors which extended into the intra- and suprasellar regions. Methods. The patients were evaluated by the same physician (P. O. L.) at regular intervals (at least twice yearly) for 2 to 10 years. Information on the sex life of the patients was obtained by careful personal case histories and, when possible, from their partners. Repeated interviews over a long period of time increased the reliability of the information. It is not possible to establish distinct criteria for the strength of the human libido, nor can sexual activity be measured directly. However, patients with sexual insufficiency caused by pituitary damage usually notice a very obvious decline in both libido and potency. This may come about rather suddenly or over the course of a few months. Therefore, in most cases it was possible for the patients to declare when their libido and potency were normal, decreased, or absent. In this presentation libido, potency, and actual sexual activity are considered together under libido/potency and recorded either as normal or decreased/absent. Data indicating atypical sexuality or genderidentity problems were also recorded. Two of the patients had definite gender-identity problems, in that they were male-to-female transsexuals. 8 Both of them had rather small intrasellar tumors and only slight signs of pituitary insufficiency. These patients were not included in the study. If necessary, the patients were given endocrine substitution therapy. Thyroxine (Levaxin) and cortisol (Hydrocortal) were given in most cases. Androgen deficiency, if present, was treated with intramuscular injections of testosterone esters in oil (Testoviron depot), 250 mg every 4th week. Hormone Assays. Prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone in serum were determined by radioimmunologic techniques. Serum prolactin levels were measured by a radioimmunosorbent technique using rabbit antihuman prolactin anti-
bodies coupled to CNBr-activated Sephadex. 9 • 1o Prolactin and antiprolactin preparations were supplied by the National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Md. FSH and LH in serum were determined by a radioimmunosorbent assay with indirectly coupled antibodies. l l The results were expressed in micrograms per liter of highly purified human pituitary FSH and LH preparations. 12 • 13 Testosterone in serum was determined with a radioimmunoassay using an antiserum to testosterone-3-oxime bovine serum albumin. 14 Because this investigation extended over several years, suitable assay methods were not originally available for all hormones studied and, as a result, data for all of these hormones are not available for all patients. Normal values for adult males in this laboratory are as follows: prolactin, less than 15 fLg/liter; FSH, 0.5 to 3.0 fLg/liter; LH, 0.4 to 3.0 fLg/liter; and testosterone, 9 to 29 nmoles/liter. LH-RH tests were performed according to the method of Lundberg and Wide. 15 An increase in serum LH of less than 0.82 fLg/liter was considered pathologically low (geometric mean, 2 SD for a control group). The results of these hormone assays and tests were related to the presence or absence of sexual problems.
RESULTS
Of the 63 patients, 48 (76.2%) reported decreased or absent libido/potency. This did not lead to medical consultation in more than one case. However, in retrospect this symptom was found to be the initial symptom in 20 patients (31.7%). The patients had been aware of their sexual problems for several years before diagnosis. A clear difference in the frequency of sexual insufficiency was found when the patients with smaller intrasellar tumors were compared with those with larger tumors which extended into the suprasellar region. In the first group, 11 (52.3%) of 21 patients had decreased or absent libido/ potency, whereas in the second group this was the case in 37 (88.1%) of 42 patients. Five of the eleven acromegalics had decreased or absent libido/potency. All of the patients with acromegaly had rather small intrasellar tumors. Fourteen of thirty-six patients had hyperprolactinemia, defined as a serum value of more than 15 fLg/liter of prolactin. Of these 14 patients, 1 had acromegaly, 4 had invasive adenomas, and the other 9 had intrasellar adenomas.
FSH ,'lg/l
LIBIDO I POTENCY normal
decreased or absent
2.0
• •
1.5
•
•
n =10
n = IS
1.0
• •
•
•••••
•
• •
:
0.5
••• - _ -It...:
-
I• ••
•• ,.
I:. 0.1
•• n =1
n = 17
•
FIG. 1. Serum FSH concentrations in 43 men with a tumor in the region of the sella turcica and normal or decreased or absent libido/potency.
The prolactin values were very high (500 to 20,000 p,g/liter) in the four patients with invasive adenomas. Only two of the fourteen patients with hyperprolactinaemia had normal libido and potency. One of these had acromegaly. Of the 22 patients with a normal serum prolactin level, 18 had decreased or absent libido/potency. There was no significant correlation (J' > 0.05) between the
prolactin level and normal or decreased/absent potency. The levels of FSH (Fig. 1) and LH (Fig. 2) in serum were correlated to the symptoms of sexual dysfunction. In Figures 1 and 2 it can be seen that the levels of LH and FSH were normal in nearly all of the men with normal libido/potency. On the other hand, most of the patients with decreased or absent libido/potency had low serum FSH and LH levels. However, 15 patients (46.8%) of 32 with decreased or absent libido/potency had normal serum FSH values, and 13 (34.2%) of 38 had normal serum LH values. LH-RH infusion tests were performed in 45 cases. The increase in serum LH was compared with that in a control group of healthy males . In 3 of 12 men with a normal LH response to LH-RH and in 32 of the 33 with a low response, decreased or absent libido/potency was reported. The correlation between the results of these tests and normal or decreased/absent libido/potency was highly significant (J' < 0.001). There was an agreement between normal and decreased basal LH levels and the LH response to LH-RH in 36 cases. In the nine tests in which the results disagreed, the LH response to LH-RH was pathologically low in eight cases and seven of these had decreased or absent libido/potency. One patient with a normal LH response from a low basal LH level had normal libido/potency. LIBIDO I POTENCY Testosterone nmolll decreased or absent normal
• •
lL LIBIDO I POTENCY
LH
,ugll
decreased or absent
normal 12
•
1.5
••
• •
1.0
•
10
••
n = 13
••
n = 11
,
•••
......
0.1
tl~ II· I:··'
• n = 25
n=L
n =1
• • •
•• ••
• •
•
••
8
6
I
0.5
177
SEXUAL FUNCTION IN MALES WITH PITUITARY TUMORS
Vol. 29, No.2
-
-
--
n=l
FIG. 2. Serum LH concentrations in 50 men with a tumor in the region of the sella turcica and normal or decreased or absent libido/potency.
2
• ••• • ••• • •• •• •
n = 31
n=L
••• • ••••• ••••••
FIG. 3. Serum testosterone concentra(ions in 40 men with a tumor in the region of the sella turcica and normal or decreased or absent libido/potency.
LUNDBERG AND WIDE
178 LH ,ugll
I ~
0.5
0.2
•
•
0.1
0.5
••
• 5
10
20 50 Testosterone nmolll
FIG. 4. Relationship between serum levels ofLH and testosterone in 37 men with a tumor in the region of the sella turcica. Open and solid symbols represent normal and decreased or absent libido/potency, respectively. Values of patients with a large tumor with extension into the suprasellar region are indicated by a square; of those with acromegaly, by a triangle; and of those with other intrasellar tumors, by a circle or dot.
The results of radioimmunoassay of serum testosterone as related to normal or decreased absent libido/potency are shown in Figure 3. In 35 of 40 patients, serum testosterone levels were below the lower limit for healthy control subjects, and were very low in most of the patients. Of 32 patients with decreased or absent libido/ potency, only 1 had a normal serum testosterone level and this was at the lower limit. Of eight patients with normal libido/potency, four had normal values and four had values which were slightly decreased. Three patients in the latter group had acromegaly. There was a significant correlation (r = 0.58, P < 0.001) between serum LH and testosterone levels (Fig. 4). LH, FSH, and testosterone levels were significantly ()' < 0.01, < 0.01, and < 0.05, respectively) higher in patients with small intrasellar tumors than in those with large tumors with suprasellar extension. DISCUSSION
The frequency of finding symptoms of reduced or absent libido/potency in patients with tumors in the region of the sella turcica will depend both on the selection of patients with regard to age and tumor characteristics and on care in taking the history. The figure obtained in the present study (7fYJhJ) is high as compared with those reported in
February 1978
most previous studies (35 to 73%); however, our figure fits well with that reported by Younghusband et al.,2 who found a similarly high frequency in patients under 40 years of age. The mean age of the patients in the present study was 44.1 years with a range of 18 to 67 years. As could be expected, the frequency of patients with symptoms of sexual dysfunction was very high (88%) in the group of patients with large tumors. However, no fewer than 52% of patients with small intrasellar tumors had reduced or absent libido/ potency. The symptoms of sexual dysfunction had been the initial symptom of the tumor in approximately 32% of the patients. However, for several reasons, males with a decrease in libido and potency seldom seek medical advice, and only 1 of the 20 patients whose sexual dysfunction was the first symptom of tumor consulted a doctor because of this symptom. In women of fertile age the initial symptom of a tumor in the sellar region is often amenorrhea, which usually leads to prompt consultation. It is well known that hyperprolactinemia is common among patients with a tumor in the sellar region. In a group of 73 patients of both sexes with tumors in the sellar region we found an increased prolactin level in 32 (44%).16 An increased prolactin level may be due to a tumor producing prolactin or to the prevention of production or transport of the hypothalamic prolactin release inhibiting factor. Prolactin seems to be essential for normal male reproduction, but elevated levels may interfere with reproductive function and cause impotence. 17• 18 The frequency of hyperprolactinemia among 30 patients with decreased or absent libido/potency in the present study was 40% and thus not higher than the frequency mentioned above for the 73 patients with pituitary tumors. Thus, in the present study there was no obvious relationship between increased prolactin levels and sexual dysfunction. It has previously been pointed out that normal FSH. and LH levels do not exclude the presence of a pituitary tumor. 19. 20 In this investigation, normal serum levels ofFSH (47%) and LH (34%) were common even among patients with reduced or absent libido/potency due to a tumor in the sellar region. The LH response to LH-RH was better related to the presence or absence of sexual dysfunction than was the basal LH level. However, determination of serum testosterone levels may be more informative about a possible endocrine etiology .of decrea8'ed or absent .libido/ potency. In the present study almost all of the
SEXUAL FUNCTION IN MALES WITH PITUITARY TUMORS
Vol. 29, No.2
patients with sexual dysfunction had low serum testosterone levels. Thus, in male patients with sexual dysfunction, the combination of a low serum testosterone level and a normal or low gonadotropin level indicates a primary disturbance in hypothalamic-pituitary function. COMMENTS ON SUBSTITUTION THERAPY WITH TESTOSTERONE
All patients were offered androgen substitution in the form of testosterone esters in a depot preparation. This treatment was started after surgery, radiotherapy, and substitution therapy with other hormones. Cortisol and thyroxine substitution alone did not normalize the sexual dysfunction. In spite of advice, five patients declined androgen therapy because they and their partners had adapted to a life without overt sexual activity and did not want any change. In 23 elderly patients androgens were not administered. In 30 patients given androgens the results were excellent with regard to libido/potency, frequency of sexual intercourse, and physical signs of androgenization. In five cases, however, the testosterone injections had little or no effect despite increases in blood testosterone levels to the normal range. REFERENCES 1. Bakay L: Results of 300 pituitary adenoma operations.
J Neurosurg 7:240, 1950 2. Younghusband OZ, Horrax G, Hurxthal LM, Hare HF, Poppen JL: Chromophobe pituitary tumors. I. Diagnosis. J Clin Endocrinol Metab 12:611, 1952 3. Heimbach SB: Follow-up studies on 105 cases of verified chromophobe and acidophile pituitary adenomata after treatment by transfrontal operation and x-ray irradiation. Acta Neurochir (Wein) 7:101, 1959 4. Fischer P-A: Hypophysenadenome. Stuttgart, Ferdinand Enke Verlag, 1963, p 1
179
5. FUrst E: On chromophobe pituitary adenoma. Acta Med Scand [Suppl] 452, 7, 1966 6. BatzdorfU, Stern WE: Clinical manifestations of pituitary adenomas: a pilot study using computer analysis. In Pituitary Tumors, Edited by PO Kohler, GT Ross, Amsterdam, Excerpta Medica, 1973, p 17 7. Lundberg PO, Drettner B, Hemmingsson A, Stenkvist B, Wide L: The invasive pituitary adenoma. A prolactinproducing tumor. Arch Neurol 34:742, 1977 8. Lundberg PO, Sjovall A, WaIinderJ: Sella turcica in maleto-female transsexuals. Arch Sex Behav 4:657, 1975 9. Wide L, Axim R, Porath J: Radioimmunosorbent assay for proteins. Chemical couplings of antibodies to insoluble dextran. Immunochemistry 4:381, 1967 10. Wide L: Radioimmunoassays employing immunosorbents. Acta Endocrinol [Suppl] (Kbh) 142:207, 1969 11. Wide L, Nillius SJ, Gemzell C, Roos P: Radioimmunosorbent assay offollicle-stimulating hormone and luteinizing hormone in serum and urine from men and women. Acta Endocrinol [Suppl] (Kbh) 174:1,1973 12. Roos P: Human follicle-stimulating hormone. Acta Endocrinol [Suppl] (Kbh) 131:1, 1968 13. Roos P, Nyberg L, Wide L, Gemzell C: Human pituitary luteinizing hormone. Isolation and characterization of four glycoproteins with luteinizing activity. Biochim Biophys Acta 405:363, 1975 14. Collins W, Mansfield M, Alladina N, Sommerville I: Radioimmunoassay of plasma testosterone. J Steroid Biochem 3:333,1972 15. Lundberg PO, Wide L: The response to TRH, LH-RH, metyrapone and vasopressin in patients with hypo. thalamo-pituitary disorders. Eur J Clin Invest 3:49, 1973 16. Lundberg PO, Wide L: UnpUblished data 17. Thorner MO, McNeilly AS, Hagan C, Besser GM: Longterm treatment of galactorrhoea and hypogonadism with bromocroptine. Br Med J 2:419, 1974 18. Franks S, Nabarro JDN, Jacobs HS: Prevalence and presentation of hyperprolactinaemia in patients with "functionless" pituitary tumours. Lancet 1:778, 1977 19. Lundberg PO: Clinical evaluation of the luteinizing hormone-releasing hormone (LH-RH) test in cases with anatomically verified disorders of the hypothalamopituitary region. Acta Neurol Scand 49:461,1973 20. Wide L: Human pituitary gonadotrophins. In Hormone Assays and Their Clinical Application, Fourth Edition, Edited by JA Loraine, ET Bell. Edinburgh, Churchill Livingstone, 1976, p 87
Vol. 29, No.2, February 1978 Prinred in U.SA.
SEXUAL FUNCTION IN MALES WITH PITUITARY TUMORS
PER OLOV LUNDBERG, M.D.* LEIF WIDE, M.D.t Departments of Neurology and Clinical Chemistry, University Hospital, S-750 14 Uppsala 14, Sweden
The frequency of decreased or absent libido/potency was studied in 65 males with tumors in the region of the sella turcica. The presence or absence of sexual dysfunction was correlated to the serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and prolactin; to the LH response toLH-releasing hormone (LH-RH); and to certain tumor characteristics. Seventy-six per cent of the patients had decreased or absent libido/potency. The corresponding figures for those with an intrasellar tumor and those with a large tumor with extention into the suprasellar region were 54% and 88%, respectively. Only 1 of 20 patients whose first symptom of a tumor was a decrease in libido or potency consulted a doctor because of this symptom. The serum levels of FSH and LH in the group of patients with decreased or absent libido/potency were within the normal range in 47% and 34%, respectively, but almost all of these patients had low serum levels of testosterone. The LH response to LH-RH was better related to the presence or absence of sexual dysfunction than was the basal LH level. There was no significant relationship between decreased or absent libido/potency and increased serum prolactin levels. A low serum testosterone level indicates an endocrine etiology of the sexual dysfunction. When combined with a normal or decreased level of gonadotropins, a primary disturbance of hypothalamic-pituitary function is probable.
It is well known that patients with pituitary tumors may have sexual problems, and the frequency with which these occur is reported to be 35% to 73% .1-6 It is believed that in many of these patients the symptoms of sexual dysfunction are due to a lack of androgen caused by a combined gonadal and adrenal gland insufficiency. However, this problem has previously been studied only superficially, and no real attempts have been made to correlate specific sexual problems directly with particular tumor properties and endocrine findings. The purpose of the present investigation was to study the occurrence and nature of sexual problems in 65 males with a tumor in the region of the sella turcica and to correlate the findings with tumor size and blood hormone levels.
EXPERUMENTALPROCEDURE
Subjects. All 65 patients were adult males, the youngest at the first examination being 18 years old. The oldest patient was 67 years old at the first examination. Four of the patients had not had a normal puberty and six of them had not undergone normal psychosexual development. The others had had a normal puberty and had had a normal adult sex life for some years. The patients were studied before and after surgery and/or radiotherapy if such procedures were performed. Twenty-nine of the patients had pituitary adenomas which extended into the intra- and suprasellar regions. Twenty-three patients had purely intrasellar tumors, and eleven of these had clinical signs of acromegaly. In four additional patients there was total destruction of the sellar region of the type seen in diffuse invasive adenomas. 7 Seven patients had craniopharyngiomas, one patient had a menil'lgioma, and one
Received August 24,1977; accepted September 12, 1977. *Professor and Head, Department of Neurology To whom reprint requests should be addressed. t Assistant Professor, Department of Clinical Chemistry.
175
I'
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LUNDBERG AND WIDE
patient had an aspergilloma; the tumors of the latter two patients extended into the sella turcica. Clinical hypoandrogenism (such as loss of beard and pubic hair, testicular atrophy, atrophy of the prostate gland, azoospermia, or even total aspermia) was found in most cases. Tumor size and localization were defined by results of skull x-ray, pneumoencephalography, and visual field studies. According to these results the patients were separated into two groups. One group comprised 23 males with purely intrasellar tumors and the other group included 42 males with larger tumors which extended into the intra- and suprasellar regions. Methods. The patients were evaluated by the same physician (P. O. L.) at regular intervals (at least twice yearly) for 2 to 10 years. Information on the sex life of the patients was obtained by careful personal case histories and, when possible, from their partners. Repeated interviews over a long period of time increased the reliability of the information. It is not possible to establish distinct criteria for the strength of the human libido, nor can sexual activity be measured directly. However, patients with sexual insufficiency caused by pituitary damage usually notice a very obvious decline in both libido and potency. This may come about rather suddenly or over the course of a few months. Therefore, in most cases it was possible for the patients to declare when their libido and potency were normal, decreased, or absent. In this presentation libido, potency, and actual sexual activity are considered together under libido/potency and recorded either as normal or decreased/absent. Data indicating atypical sexuality or genderidentity problems were also recorded. Two of the patients had definite gender-identity problems, in that they were male-to-female transsexuals. 8 Both of them had rather small intrasellar tumors and only slight signs of pituitary insufficiency. These patients were not included in the study. If necessary, the patients were given endocrine substitution therapy. Thyroxine (Levaxin) and cortisol (Hydrocortal) were given in most cases. Androgen deficiency, if present, was treated with intramuscular injections of testosterone esters in oil (Testoviron depot), 250 mg every 4th week. Hormone Assays. Prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone in serum were determined by radioimmunologic techniques. Serum prolactin levels were measured by a radioimmunosorbent technique using rabbit antihuman prolactin anti-
bodies coupled to CNBr-activated Sephadex. 9 • 1o Prolactin and antiprolactin preparations were supplied by the National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Md. FSH and LH in serum were determined by a radioimmunosorbent assay with indirectly coupled antibodies. l l The results were expressed in micrograms per liter of highly purified human pituitary FSH and LH preparations. 12 • 13 Testosterone in serum was determined with a radioimmunoassay using an antiserum to testosterone-3-oxime bovine serum albumin. 14 Because this investigation extended over several years, suitable assay methods were not originally available for all hormones studied and, as a result, data for all of these hormones are not available for all patients. Normal values for adult males in this laboratory are as follows: prolactin, less than 15 fLg/liter; FSH, 0.5 to 3.0 fLg/liter; LH, 0.4 to 3.0 fLg/liter; and testosterone, 9 to 29 nmoles/liter. LH-RH tests were performed according to the method of Lundberg and Wide. 15 An increase in serum LH of less than 0.82 fLg/liter was considered pathologically low (geometric mean, 2 SD for a control group). The results of these hormone assays and tests were related to the presence or absence of sexual problems.
RESULTS
Of the 63 patients, 48 (76.2%) reported decreased or absent libido/potency. This did not lead to medical consultation in more than one case. However, in retrospect this symptom was found to be the initial symptom in 20 patients (31.7%). The patients had been aware of their sexual problems for several years before diagnosis. A clear difference in the frequency of sexual insufficiency was found when the patients with smaller intrasellar tumors were compared with those with larger tumors which extended into the suprasellar region. In the first group, 11 (52.3%) of 21 patients had decreased or absent libido/ potency, whereas in the second group this was the case in 37 (88.1%) of 42 patients. Five of the eleven acromegalics had decreased or absent libido/potency. All of the patients with acromegaly had rather small intrasellar tumors. Fourteen of thirty-six patients had hyperprolactinemia, defined as a serum value of more than 15 fLg/liter of prolactin. Of these 14 patients, 1 had acromegaly, 4 had invasive adenomas, and the other 9 had intrasellar adenomas.
FSH ,'lg/l
LIBIDO I POTENCY normal
decreased or absent
2.0
• •
1.5
•
•
n =10
n = IS
1.0
• •
•
•••••
•
• •
:
0.5
••• - _ -It...:
-
I• ••
•• ,.
I:. 0.1
•• n =1
n = 17
•
FIG. 1. Serum FSH concentrations in 43 men with a tumor in the region of the sella turcica and normal or decreased or absent libido/potency.
The prolactin values were very high (500 to 20,000 p,g/liter) in the four patients with invasive adenomas. Only two of the fourteen patients with hyperprolactinaemia had normal libido and potency. One of these had acromegaly. Of the 22 patients with a normal serum prolactin level, 18 had decreased or absent libido/potency. There was no significant correlation (J' > 0.05) between the
prolactin level and normal or decreased/absent potency. The levels of FSH (Fig. 1) and LH (Fig. 2) in serum were correlated to the symptoms of sexual dysfunction. In Figures 1 and 2 it can be seen that the levels of LH and FSH were normal in nearly all of the men with normal libido/potency. On the other hand, most of the patients with decreased or absent libido/potency had low serum FSH and LH levels. However, 15 patients (46.8%) of 32 with decreased or absent libido/potency had normal serum FSH values, and 13 (34.2%) of 38 had normal serum LH values. LH-RH infusion tests were performed in 45 cases. The increase in serum LH was compared with that in a control group of healthy males . In 3 of 12 men with a normal LH response to LH-RH and in 32 of the 33 with a low response, decreased or absent libido/potency was reported. The correlation between the results of these tests and normal or decreased/absent libido/potency was highly significant (J' < 0.001). There was an agreement between normal and decreased basal LH levels and the LH response to LH-RH in 36 cases. In the nine tests in which the results disagreed, the LH response to LH-RH was pathologically low in eight cases and seven of these had decreased or absent libido/potency. One patient with a normal LH response from a low basal LH level had normal libido/potency. LIBIDO I POTENCY Testosterone nmolll decreased or absent normal
• •
lL LIBIDO I POTENCY
LH
,ugll
decreased or absent
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•
1.5
••
• •
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•
10
••
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••
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,
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• • •
•• ••
• •
•
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177
SEXUAL FUNCTION IN MALES WITH PITUITARY TUMORS
Vol. 29, No.2
-
-
--
n=l
FIG. 2. Serum LH concentrations in 50 men with a tumor in the region of the sella turcica and normal or decreased or absent libido/potency.
2
• ••• • ••• • •• •• •
n = 31
n=L
••• • ••••• ••••••
FIG. 3. Serum testosterone concentra(ions in 40 men with a tumor in the region of the sella turcica and normal or decreased or absent libido/potency.
LUNDBERG AND WIDE
178 LH ,ugll
I ~
0.5
0.2
•
•
0.1
0.5
••
• 5
10
20 50 Testosterone nmolll
FIG. 4. Relationship between serum levels ofLH and testosterone in 37 men with a tumor in the region of the sella turcica. Open and solid symbols represent normal and decreased or absent libido/potency, respectively. Values of patients with a large tumor with extension into the suprasellar region are indicated by a square; of those with acromegaly, by a triangle; and of those with other intrasellar tumors, by a circle or dot.
The results of radioimmunoassay of serum testosterone as related to normal or decreased absent libido/potency are shown in Figure 3. In 35 of 40 patients, serum testosterone levels were below the lower limit for healthy control subjects, and were very low in most of the patients. Of 32 patients with decreased or absent libido/ potency, only 1 had a normal serum testosterone level and this was at the lower limit. Of eight patients with normal libido/potency, four had normal values and four had values which were slightly decreased. Three patients in the latter group had acromegaly. There was a significant correlation (r = 0.58, P < 0.001) between serum LH and testosterone levels (Fig. 4). LH, FSH, and testosterone levels were significantly ()' < 0.01, < 0.01, and < 0.05, respectively) higher in patients with small intrasellar tumors than in those with large tumors with suprasellar extension. DISCUSSION
The frequency of finding symptoms of reduced or absent libido/potency in patients with tumors in the region of the sella turcica will depend both on the selection of patients with regard to age and tumor characteristics and on care in taking the history. The figure obtained in the present study (7fYJhJ) is high as compared with those reported in
February 1978
most previous studies (35 to 73%); however, our figure fits well with that reported by Younghusband et al.,2 who found a similarly high frequency in patients under 40 years of age. The mean age of the patients in the present study was 44.1 years with a range of 18 to 67 years. As could be expected, the frequency of patients with symptoms of sexual dysfunction was very high (88%) in the group of patients with large tumors. However, no fewer than 52% of patients with small intrasellar tumors had reduced or absent libido/ potency. The symptoms of sexual dysfunction had been the initial symptom of the tumor in approximately 32% of the patients. However, for several reasons, males with a decrease in libido and potency seldom seek medical advice, and only 1 of the 20 patients whose sexual dysfunction was the first symptom of tumor consulted a doctor because of this symptom. In women of fertile age the initial symptom of a tumor in the sellar region is often amenorrhea, which usually leads to prompt consultation. It is well known that hyperprolactinemia is common among patients with a tumor in the sellar region. In a group of 73 patients of both sexes with tumors in the sellar region we found an increased prolactin level in 32 (44%).16 An increased prolactin level may be due to a tumor producing prolactin or to the prevention of production or transport of the hypothalamic prolactin release inhibiting factor. Prolactin seems to be essential for normal male reproduction, but elevated levels may interfere with reproductive function and cause impotence. 17• 18 The frequency of hyperprolactinemia among 30 patients with decreased or absent libido/potency in the present study was 40% and thus not higher than the frequency mentioned above for the 73 patients with pituitary tumors. Thus, in the present study there was no obvious relationship between increased prolactin levels and sexual dysfunction. It has previously been pointed out that normal FSH. and LH levels do not exclude the presence of a pituitary tumor. 19. 20 In this investigation, normal serum levels ofFSH (47%) and LH (34%) were common even among patients with reduced or absent libido/potency due to a tumor in the sellar region. The LH response to LH-RH was better related to the presence or absence of sexual dysfunction than was the basal LH level. However, determination of serum testosterone levels may be more informative about a possible endocrine etiology .of decrea8'ed or absent .libido/ potency. In the present study almost all of the
SEXUAL FUNCTION IN MALES WITH PITUITARY TUMORS
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patients with sexual dysfunction had low serum testosterone levels. Thus, in male patients with sexual dysfunction, the combination of a low serum testosterone level and a normal or low gonadotropin level indicates a primary disturbance in hypothalamic-pituitary function. COMMENTS ON SUBSTITUTION THERAPY WITH TESTOSTERONE
All patients were offered androgen substitution in the form of testosterone esters in a depot preparation. This treatment was started after surgery, radiotherapy, and substitution therapy with other hormones. Cortisol and thyroxine substitution alone did not normalize the sexual dysfunction. In spite of advice, five patients declined androgen therapy because they and their partners had adapted to a life without overt sexual activity and did not want any change. In 23 elderly patients androgens were not administered. In 30 patients given androgens the results were excellent with regard to libido/potency, frequency of sexual intercourse, and physical signs of androgenization. In five cases, however, the testosterone injections had little or no effect despite increases in blood testosterone levels to the normal range. REFERENCES 1. Bakay L: Results of 300 pituitary adenoma operations.
J Neurosurg 7:240, 1950 2. Younghusband OZ, Horrax G, Hurxthal LM, Hare HF, Poppen JL: Chromophobe pituitary tumors. I. Diagnosis. J Clin Endocrinol Metab 12:611, 1952 3. Heimbach SB: Follow-up studies on 105 cases of verified chromophobe and acidophile pituitary adenomata after treatment by transfrontal operation and x-ray irradiation. Acta Neurochir (Wein) 7:101, 1959 4. Fischer P-A: Hypophysenadenome. Stuttgart, Ferdinand Enke Verlag, 1963, p 1
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5. FUrst E: On chromophobe pituitary adenoma. Acta Med Scand [Suppl] 452, 7, 1966 6. BatzdorfU, Stern WE: Clinical manifestations of pituitary adenomas: a pilot study using computer analysis. In Pituitary Tumors, Edited by PO Kohler, GT Ross, Amsterdam, Excerpta Medica, 1973, p 17 7. Lundberg PO, Drettner B, Hemmingsson A, Stenkvist B, Wide L: The invasive pituitary adenoma. A prolactinproducing tumor. Arch Neurol 34:742, 1977 8. Lundberg PO, Sjovall A, WaIinderJ: Sella turcica in maleto-female transsexuals. Arch Sex Behav 4:657, 1975 9. Wide L, Axim R, Porath J: Radioimmunosorbent assay for proteins. Chemical couplings of antibodies to insoluble dextran. Immunochemistry 4:381, 1967 10. Wide L: Radioimmunoassays employing immunosorbents. Acta Endocrinol [Suppl] (Kbh) 142:207, 1969 11. Wide L, Nillius SJ, Gemzell C, Roos P: Radioimmunosorbent assay offollicle-stimulating hormone and luteinizing hormone in serum and urine from men and women. Acta Endocrinol [Suppl] (Kbh) 174:1,1973 12. Roos P: Human follicle-stimulating hormone. Acta Endocrinol [Suppl] (Kbh) 131:1, 1968 13. Roos P, Nyberg L, Wide L, Gemzell C: Human pituitary luteinizing hormone. Isolation and characterization of four glycoproteins with luteinizing activity. Biochim Biophys Acta 405:363, 1975 14. Collins W, Mansfield M, Alladina N, Sommerville I: Radioimmunoassay of plasma testosterone. J Steroid Biochem 3:333,1972 15. Lundberg PO, Wide L: The response to TRH, LH-RH, metyrapone and vasopressin in patients with hypo. thalamo-pituitary disorders. Eur J Clin Invest 3:49, 1973 16. Lundberg PO, Wide L: UnpUblished data 17. Thorner MO, McNeilly AS, Hagan C, Besser GM: Longterm treatment of galactorrhoea and hypogonadism with bromocroptine. Br Med J 2:419, 1974 18. Franks S, Nabarro JDN, Jacobs HS: Prevalence and presentation of hyperprolactinaemia in patients with "functionless" pituitary tumours. Lancet 1:778, 1977 19. Lundberg PO: Clinical evaluation of the luteinizing hormone-releasing hormone (LH-RH) test in cases with anatomically verified disorders of the hypothalamopituitary region. Acta Neurol Scand 49:461,1973 20. Wide L: Human pituitary gonadotrophins. In Hormone Assays and Their Clinical Application, Fourth Edition, Edited by JA Loraine, ET Bell. Edinburgh, Churchill Livingstone, 1976, p 87
