2 Gonadal and adrenal androgen secretion in hirsute females

2 Gonadal and Adrenal Androgen Secretion in Hirsute Females L. M O L T Z U. SCHWARTZ

Hirsutism and related symptoms may be due to (1) glandular causes, i.e. non-tumorous and tumorous ovarian and/or adrenal hypersecretion of androgenic steroids (2) extraglandular causes, i.e. increased peripheral conversion of preandrogens, decreased specific plasma androgen binding, target organ hypersensitivity, or administration of androgenic drugs or (3) a combination of any of these factors. Numerous methods have been used to verify the presence of excess androgens and to determine their origin (Maroulis, 1981). Depending on the number of steroids analysed, elevated peripheral levels of at least one androgen can be demonstrated in more than 90% of cases. However, the type, frequency, and extent of abnormalities vary considerably. None of the circulating androgens has an exclusive gonadal or adrenal source. Plasma concentrations reflect the sum of entry into circulation from glandular secretion and extraglandular tissue production, as well as their hepatic and extrahepatic clearance. Thus, the measurement of peripheral steroids does not allow the determination of their site of origin. The estimation of secretion rates is complicated by the complexities of ovarian and adrenal steroidogenesis. Multiple variables have to be taken into account, e.g. episodic, diurnal, cyclic and age-related variations. GENERAL METHODOLOGICAL CONSIDERATIONS

Various approaches have been utilized to study glandular secretion in hirsute females; however, all of these methods are associated with limited validity and provide only semiquantitative estimates of momentary secretory activity (Baird, 1976; James et al, 1976). Isotope dilution techniques yield approximations of the total blood production rates from the measurement of plasma concentrations and metabolic clearance rates; they cannot identify the gonadal and adrenal contributions. This requires additional analysis of samples obtained Clinics in Endocrinology and Metabolism--Vol.

15, No. 2, May 1986

229

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L. MOLTZ AND U. SCHWARTZ

directly from the respective effluent veins, or operative removal, or specific suppression of secretion of either pair of glands. These methods have several disadvantages, such as the infusion of radioactive steroids, the extrapolation to 24-hour values from shorter investigation periods and the variations of hepatic blood flow and metabolic clearance rate introduced by posture and food intake (Vermeulen, 1983). Dynamic function tests have been suggested for the differentiation between ovarian and gonadal androgen secretion. They include the supposedly specific stimulation of non-tumorous ovaries and adrenals with human chorionic gonadotropin (hCG) or adrenoeorticotrophic hormone (ACTH) as well as their suppression with oral contraceptives or glucocorticoids. Lack of suppressibility, on the other hand, is commonly regarded as a distinctive feature of autonomous androgen-secreting turnouts. However, it was shown in our laboratory that function tests cannot reliably discriminate between steroids of ovarian and adrenal origin due to non-specific pharmacodynamic effects (Moltz et al, 1982). In addition, oestrogen-suppressible ovarian and glucocorticoid-suppressible adrenal neoplasms, as well as ACTH-responsive ovarian and hCG-responsive adrenal tumours, have been described (Moltz et al, 1984a). Finally, selective catheterization techniques have been devised to study directly glandular secretion. This combined radiological-endocrinological procedure involves retrograde transfemoral sampling of both ovarian and adrenal veins and determination of their androgen content. Demonstration of a gradient between glandular effluent levels and peripheral concentrations establishes secretion. Yet this method is also associated with difficulties and potentially significant errors: inability to calculate secretion rates without determination of actual glandular blood flow during the procedure; ignorance of intraglandular androgen metabolism; variable influences of premedication, stress and application of contrast medium on secretion; problems related to the correct identification of glandular veins and accurate placement of the catheter resulting in admixture of peripheral blood (S6rensen et al, 1985). Nevertheless, this method provides useful information on ovarian and adrenal androgen secretion.

SELECTIVE CATHETERIZATION TECHNIQUE The data presented in this review are restricted to those obtained by selective catheterization performed in 60 patients with non-tumorous hyperandrogenism and seven patients with androgen-secreting ovarian neoplasms (Moltz et al, 1984a,b). In addition, eight healthy volunteers with proven ovulatory cycles were investigated to define the upper limits of normal secretion (Moltz et al, 1984c). All subjects gave informed written consent to these studies. Catheterization was not associated with any serious complications; minor adverse reactions occurred in only seven patients.

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231

The following standardized protocol was used. The procedure was always carried out between 8:00 a.m. and 10:00 a.m. to reduce the interference from circadian variations of androgen secretion. In those women with regular menses and oligomenorrhoea (n = 48), it was performed during the early follicular phase (days 3 to 7). A Cobra catheter (internal diameter, 1.17 ram) was introduced under local anaesthesia via a femoral vein. No premedication was given to avoid iatrogenic suppression of adrenal steroid output. Serial blood samples were obtained from the orifices of both adrenal and both ovarian veins to compensate for episodic variations of steroid secretion. Steroid levels determined in samples considered subselective by radiographic criteria were disregarded. In the androgenized patients, samples were drawn both before and 20 to 30 minutes after intravenous injection of 8 to 12 mg of dexamethasone. The following serum steroids were determined by radioimmunoassay as previously described (Moltz et al, 1984b; Moltz et al, 1984c): testosterone (T), dihydrotestosterone (DHT), androstenedione (A4-A), dehydroepiandrosterone (DHA), dehydroepiandrosterone sulphate (DHAS), 17ahydroxyprogesterone (17P), cortisol (F). Steroid gradients, i.e., the differences between ovarian as well as adrenal and peripheral vein levels (OPG, APG), served as semiquantitative estimates of momentary secretory activity. Active secretion was assumed when glandular effluent values were significantly higher than the corresponding peripheral values (P<0.05). A N D R O G E N S E C R E T I O N IN N O R M A L W O M E N

In the past, interpretation of catheterization findings in hirsute patients was often speculative due to the absence of information regarding androgen gradients in healthy women with ovulatory cycles. Our own studies (Moltz et al, 1984c; Table 1) revealed that the gonads do not secrete significant amounts of T during the early follicular phase. Similar findings were made in five women who were catheterized intraoperatively (Horton et al, 1966). Although in vitro studies have demonstrated the capacity of the human follicle to synthesize androgens (McNatty et al, 1979), the in vivo data demonstrate that this potential is not utilized at the beginning of the cycle. Our observation also contradicts the reported ovarian contribution of 33-66% to the circulating T pool assumed for this stage on the basis of peripheral T changes after dexamethasone administration (Genazzani et al, 1977; Vermeulen et al, 1979). The discrepancy is understandable in view of the non-specificity of glucocorticoid suppression tests (Moltz et al, 1982). In contrast to the absence of gonadal T, D H T and F secretion, the ovaries did generate significant quantities of A4-A, D H A and 17P between days 3 and 7 of the cycle. To our knowledge, the observation of significant OPGs for D H A S in two individuals is the first direct evidence for its partially gonadal origin. It explains the cyclic changes of DHAS reported in an adrenalectomized woman (Abraham et al, 1973).

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L. MOLTZ AND U. SCHWARTZ

The adrenals were considerably more active than the gonads during the early follicular phase; this was apparent for all seven steroids measured. Previously it had been thought that D H T arises exclusively from peripheral conversion of A4-A and T (Ito et al, 1970; Vermeulen et al, 1979). Our study indicates that D H T is directly secreted by normal adrenals, thus supporting in Vitro findings (Maroulis et al, 1980). The adrenal DHAS gradients are relatively small despite a high production rate; they reflect the low metabolic clearance rate characteristic of this steroid (Vermeulen et al, 1979). Random, non-simultaneous catheterization of the four glandular veins revealed no significant differences between the respective effluent concentrations on the left and on the right side. It appears that the ovaries have parallel androgen secretion during the early follicular phase; the same applies to adrenal steroid output. Discordant bilateral levels have been reported by other investigators; non-parallel ovarian hormone production is to be expected in the presence of preovulatory follicles or a corpus luteum (Wentz et al, 1976), while dissimilar adrenal values may result from unpredictable pulsing (Nicolis et al, 1974; Eisenberg, 1979). The problems of data interpretation due to the episodic, circadian and cyclic variations of glandular steroidogenesis can be overcome by serial sampling and uniform timing of the procedure. ANDROGEN SECRETION IN NON-TUMOROUS HYPERANDROGENISM

The type, frequency, and extent of hormonal changes varied considerably between the androgenized patients. The degree of deviation did not correlate to either the severity of symptoms or the laparoscopic, angiographic, or histological findings. The wide range of individual concentrations of T and DHAS measured in the peripheral vein as well as in the four glandular effluents is depicted in Figure 1. There was a considerable overlap of T and DHAS levels between healthy and hirsute women in every vessel. This observation also applied to the variations of DHT, A4-A, D H A , 17P, and F levels. Compared with the normal cohort (early follicular phase), the mean levels of all steroids, except F, in peripheral blood were significantly elevated in the women with non-neoplastic hyperandrogenism as a group (P<0.05). Peripheral concentrations of T and DHAS during catheterization were above normal in about one-third of the cases, whereas A4-A, DHA, and 17P were increased in about half of the patients (Figure 2). Peripheral hyperandrogenaemia was evident in only 63% when hormone analysis was restricted to the measurement of Peripheral T and DHAS; however, almost 90% of patients showed abnormalities when all seven steroids were taken into consideration. The steroid gradients in hirsute patients reflecting glandular secretion are given in Table 1. During the early follicular phase, all hormones assayed were released bilaterally in parallel fashion by the gonads and

233

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non-neoplastic hyperandrogenism (PV, peripheral; ROV, right ovarian; LOV, left ovarian; RAV, right adrenal; LAV, left adrenal veins). Only values from selective samples are included; hatched areas demarcate the upper 95% confidence limits of normal; triangles denote patients with histologicallyproven hyperthecosis (n = 10). From Moltz et al (1984b), reproduced with permission of the publisher, The American Fertility Society.

adrenals. The ovaries and adrenals of these patients as a group produced significant quantities of T, D H T , A4-A, D H A , and 17P (significance of differences between glandular and peripheral vein levels, P<0.001); D H A S and F were secreted by the adrenals only. The observed negative OPGs for D H A S and F imply gonadal utilization and metabolism; however, they may also be artifacts due to episodic fluctuations. Our findings documenting the direct ovarian and adrenal secretion of D H T in hirsute women confirm preliminary results presented by Maroulis et al (1975). In absolute terms, adrenal steroid release was significantly greater than gonadal steroid output during the early follicular phase; this applied to all seven hormones assayed (P<0.001)2 Compared with the group of healthy women, the mean O P G s for T, A -A, D H A , and 17P, as well as the A P G for 17P, surpassed the upper limit of normal; yet these differences in group behaviour were significant only in regard to gonadal

234

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output of 17P (P<0.05). In contrast, evaluation of each individual case showed that glandular hypersecretion of at least one androgen, i.e. T, DHT, A4-A, D H A , or DHAS was present in 80%. However, it did not necessarily result in an increase of peripheral levels. This may be due to dilutional effects as well as the reported rise of metabolic clearance rates in hirsute women (Maroulis, 1981). Moreover, the aberrations were often minor and restricted to a limited number of patients and/or a single hormone. For instance, direct ovarian release of DHAS was present in merely six women and, therefore, was not reflected in the overall group behaviour. The differentiation between ovarian, adrenal, and combined ovarianadrenal hyperandrogenism of non-neoplastic origin was made on the basis of our previous catheterization findings in healthy women. Excess ovarian and/or adrenal androgen output was assumed in a given individual when one or more of the respective T, DHT, A4-A, DHA, and DHAS gradients exceeded the upper 95% confidence limits of normal. Combined hypersecretion (41%) was the most frequent cause; purely ovarian (27%) or adrenal overproduction (12%) were identified less often; normal glandular androgen output was found in 20% of patients. The relative incidence of ovarian and/or adrenal involvement in the aetiology of non-neoplastic hyperandrogenism is still a debated issue. Regardless of the diagnostic approach, the distribution patterns reported in the literature vary extremely (Cruikshank et al, 1971; Kirschner et al, 1971; Stahl et al, 1973; Abraham et al, 1978) (Table 2). Abraham and Manlimos (1978) have been among the advocates of a predominantly adrenal site of androgen

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Table 2. Relative percentage frequency of ovarian, adrenal, and combined ovarian-adrenal non-neoplastic hyperandrogenism reported in the literature. From Moltz et al (1984b), reproduced with permission of the publisher, The American Fertility Society. Authors

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*Diagnostic procedure: FT, dynamic function tests; SC, selective catheterization. hypersecretion. Their classification was based on the results of long-term dexamethasone suppression tests. However, it has been documented directly that glucocorticoids may significantly reduce not only adrenal, but also ovarian androgen secretion (Moltz et al, 1982). Kirschner and Jacobs (1971) suggested a preponderance of ovarian hyperandrogenism on the basis of catheterization data. Their study was restricted to the measurement of effluent T, A4-A, and F levels and hampered by the lack of healthy control subjects. Their calculation of androgen secretion rates was based on several assumptions, which were later shown to be erroneous (Vermeulen and Rubens 1979), including parallel secretion of F and adrenal androgens, normal F output during radiography of premedicated patients, and constant peripheral conversion of androgen precursors. In addition, they only differentiated between ovarian and adrenal sources, neglecting the possibility of combined dysfunction. The present investigation relies on established normal steroid gradients. It indicated that excessive glandular androgen release often has a mixed ovarian-adrenal origin, which only becomes evident when a broad spectrum of steroids is analysed. The close interaction between gonads and adrenals is underlined by numerous reports in the literature (Goldzieher, 1981; Korth-Schtitz et al, 1974; Lobo et al, 1980) documenting (1) the induction of ovulation by glucocorticoid therapy (2) the stimulation of adrenal steroidogenesis by oestrogen administration and (3) the coexistence of both adrenal and ovarian non-neoplastic as well as neoplastic hyperandrogenism. The validity of our results regarding incidence rates is limited by the small number of control subjects, single effluent sampling in the patients, as opposed to serial sampling in the healthy volunteers, and a definition of 'normal' based exclusively on early follicular phase data.

Polycystic ovary syndrome (PCO) It is still a matter of controversy whether the presence of polycystic ovaries constitutes a nosological entity or a non-specific morphologic substrate associated with hyperandrogenism. During our study all hirsute women underwent laparoscopy to rule out a macroscopicaUy visible ovarian neoplasm. Changes suggestive of polycystic ovary syndrome were detected in 33 patients, i.e. a thickened and whitish cortex, multiple subcapsular cysts and gross gonadal enlargement.

ANDROGEN SECRETION IN HIRSUTE FEMALES

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3. Individual percentage increases of elevated ovarian- and adrenal-peripheral vein gradients (OPG, APG) in 33 patients with polycysticovaries (>mean + 2 standard deviations of eight normal control subjects). From Moltz et al (1985), with permission.

T h e r e was no correlation between morphological, clinical and endocrine changes; a PCO-specific hormonal pattern was not identifiable (Moltz et al, 1985). Analysis of gradient data obtained by selective catheterization revealed that combined ovarian-adrenal androgen hypersecretion was present in 46% of PCO cases; purely ovarian (21%) or adrenal (12%) overproduction were not as frequent. This pattern of distribution concerning aetiology does not differ significantly from that observed in patients without laparoscopic signs of PCO (n = 17; Moltz et al, 1985). Gradient evaluation in each individual case showed that glandular hypersecretion of at least one androgen was present in 80% (Figure 3). Again, the percentage incidences of elevated OPGs and A P G s do not deviate substantially from those found in the whole group of patients with non-tumorous hyperandrogenism (n = 60; Moltz et al, 1984b). Figure 4 illustrates the non-specific suppression of ovarian and adrenal secretion of T and D H A S by dexamethasone in both cohorts with and

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L. MOLTZ AND U. SCHWARTZ

without PCO. Qualitatively similar results applied to the other steroids measured. These data dearly indicate that glucocorticoid suppression tests cannot reliably discriminate between ovarian and adrenal non-tumorous hyperandrogenism due to extremely variable individual responsiveness. Ovarian hyperthecosis Hyperthecosis has repeatedly been described as a tumour-like disease entity separate from PCO and characterized by a pathognomonic histology (i.e. stromal versus perifollicular theca cell hyperplasia and luteinization) as well as distinct clinical and endocrine features, e.g. obligatory signs of virilization and excess ovarian androgen secretion without :significant adrenal contribution (Karam ~and Hajj, 1979). This assertion remains a topic of debate. The present investigation included 10 patients with histologically proven hyperthecosis (Scnlly, 1979). The clinical and biochemical findings were as inconsistent as in PCO (Schwartz et al, 1985). For example, peripheral T levels varied between 0.4 and 2.5 ng/ml before and during catheterization. Figure 5 shows the overlap of testosterone levels in peripheral and glandular effluent blood between healthy women and patients with hyperthecosis as well as androgen-secreting ovarian neoplasms. In four individuals, ovarian testosterone secretion fell within the tumorous range (Moltz et al, 1984a). Gradient analysis of all androgens indicated purely ovarian hypersecretion in six patients, but also an additional significant adrenal involvement in four women. As in PCO, dexamethasone suppressed gonadal as well as adrenal androgen output. ANDROGEN SECRETION IN TUMOROUS HYPERANDROGENISM Androgen-secreting ovarian or adrenal neoplasms, although rare, may be the underlying cause of virilism and related symptoms. Neoplastic hyperandrogenism has to be ruled out in women with severe, sudden/late onset, and/or progressive hirsutism. It must also be suspected if other signs of virilism are present (e.g. temporal balding, deepening of the voice, clitoromegaly, and male body habitus). During the past decade, selective catheterization has been used to study glandular secretion in several ovarian and adrenal androgen-secreting turnouts (Moltz et al, 1984a). However, representative secretion patterns or criteria demarcating non-tumorous and tumorous hyperandrogenism could not be established since these investigations constituted single case reports. It has to be acknowledged that our own catheterization experience with histologically proven adrenal neoplasms is nil. From the literature it appears that virilizing adrenal tumours secrete predominantly either T or DHAS, although simultaneous elevated output of A4-A and D H A was also described. Since gonadal vein sampling was not performed in any of these cases investigated by preoperative catheterization, information concerning the potential involvement of ovarian hypersecretion is not available.

239

A N D R O G E N SECRETION IN HIRSUTE FEMALES PCO (n = 33)

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gradients (OPG, APG) for testosterone (T) and D H A sulphate (DHAS) before and after intravenous dexamethasone in hirsute patients with and without polycystic ovaries (PCO). From Moltz et al (1985), with permission.

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L. MOLTZ AND U. SCHWARTZ

Tng/ml

Figure 5. Individualperipheral and glandularvein levels of T in 10 patients with hyperthecosis (denoted by triangles) and 7 patients with androgen-secretinggonadal tumours (denoted by dots). Only values from selective samples are included (PV, peripheral; ROV, right ovarian; LOV, left ovarian; RAV, right adrenal; LAV, left adrenal veins; hatched areas demarcatethe upper 95% confidencelimits of normal).

However, the presence of an adrenal adenoma in addition to hyperthecosis has been reported (Trost et al, 1981). The non-specific response of adrenal tumours to glucocorticoid suppression and gonadotropin stimulation has already been referred to (Matthews et al, 1972, Larson et al, 1976, Mack et al, 1978). In the present study, standardized bilateral ovarian-adrenal vein catheterization was utilized to preoperatively assess glandular steroid release in seven consecutive cases of occult virilizing gonadal neoplasms (Moltz et al, 1984a). Histological evaluation of the implicated ovaries revealed three lipid cell, two Leydig cell, and two Sertoli-Leydig cell tumours, respectively, measuring between 0.6 and 2.2 cm in diameter. Endoscopy and radiography failed to locate the functional lesions. Prior to catheterization, peripheral T surpassed the upper 95% confidence limit of the non-tumorous group, i.e. 1.5 ng/ml, in all instances; in one patient it was below this critical value during catheterization This may indicate unpredictable episodic T secretion by neoplastic gonadal

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A N D R O G E N SECRETION IN HIRSUTE FEMALES

lesions. Antecubital vein DHT exceeded the non-tumorous range in two subjects. The peripheral concentrations of the other steroids fell within the non-neoplastic range in all instances. Selective cannulation of ovarian veins was accomplished in six cases, displaying a unilateral increase of T in the effluent draining the neoplastic gonad (Figure 6) which exceeded the upper 95% confidence limit of the non-tumorous group, i.e. 2.7 ng/ml. In the remaining patient, gradient analysis ruled out an adrenal tumour, but did not facilitate lateralization of the gonadal lesion due to unsatisfactory ovarian effluent sampling. In addition to the consistent hypersecretion of T, variable excess gonadal output of DHT, An-A, D H A , and 17P was evident. These functional gland abnormalities were not correlated to tumour morphology. Thus, the hypothesis cannot be confirmed that A4-A is the predominant secretory T

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product of ovarian lipid cell tumours, while Leydig cell tumours primarily generate T (Mandel et al, 1981). Neoplastic ovarian hypersecretion was associated with adrenal androgenic hyperfunction in three women; similar biglandular involvement has previously been observed in a patient with a Sertoli-Leydig cell tumour (Cruikshank et al, 1974). Intravenous bolus administration of 12 mg of dexamethasone (n = 4) significantly reduced not only the testosterone output, but also the release of A4-A, DHA and 17P by the neoplastic gonads. Suppression of adrenal secretion of DHT, 17P and F was observed, while the adrenal-peripheral vein gradients for T remained paradoxically unaffected. In conclusion, no correlation was found between any of the following parameters: peripheral or glandular vein steroid levels, androgen gradients, seVerity of symptoms, tumour morphology, and tumour size. CLINICAL IMPLICATIONS At present, selective bilateral ovarian-adrenal vein catheterization appears to be the most sensitive method available for the semiquantitative estimation of glandular androgen secretion. It is the only technique allowing separate analysis of each gonad and adrenal, respectively. The procedure is reliable and safe provided that it is performed at centres with adequate experience, under strictly standardized conditions to reduce the interference of episodic, circadian and cyclic variations of steroidogenesis. Stimulation and suppression tests cannot reliably differentiate between ovarian and adrenal, non-tumorous and tumorous hyperandrogenism due to frequently occurring non-specific pharmacodynamic effects. An appraisal of all our 75 catheterizations Shows that the evolutionary pathophysiology of glandular androgen hypersecretion from normal to non-tumorous conditions to neoplastic disease must be regarded as a continuous process without sharp borderlines. It appears from these data that the presence of hirsutism and related symptoms was associated with excess glandular androgen release in at least 80%. Combined hypersecretion (41%) was the most frequent cause; purely ovarian (27%) or adrenal overproduction (12%) were identified less often. Although scientifically interesting, the differentiation between the various aetiological subgroups of non-tumorous hyperandrogen{sm has become dispensable due to the availability of antiandrogens, such as cyproterone acetate and spironolactone, The polycystic ovary syndrome represents a non-specific, nonobligatory morphologic substrate of hyperandrogenism rather than a nosological entity. Ovarian hyperthecosis is a tumour-like condition which cannot be reliably separated from gonadal neoplasms by biochemical means. The preoperative verification and localization of a virilizing neoplasm is of utmost clinical importance. It may reduce the need for operative exploration and may help in selecting the adequate surgical approach. Our present diagnostic and therapeutic concept is founded on the upper 95% confidence limits of the androgen values measured in peripheral and

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243

glandular vein blood of our non-neoplastic cohort. T and DHAS appear to be the most useful markers, because androgen-secreting ovarian or adrenal neoplasms without peripheral elevation of either steroid hardly ever occur (Maroulis, 1981). Women with mild, early onset, non-progressive hirsutism and ache do not require a peripheral androgen screen. In such cases, antiandrogen therapy may be initiated without prior verification of the presence or determination of the source of excess androgens (Moltz et al, 1984b). Basal T should be assessed by a multiple sampling technique (Goldzieher et al, 1976) in all patients with moderate to severe, abrupt or late onset and progressive hirsutism or other signs of virilism. Elevations of peripheral androgens suggestive of a neoplastic ovarian or adrenal lesion include T levels >1.5 ng/ml (Moltz et al, 1984b) and/or DHAS concentrations >9000 ng/ml (Maroulis, 1981). The guideline regarding peripheral T only applies when highly specific assays are used which yield upper normal limits <0.7 ng/ml. Unfortunately, many of the commercially available kits do not fulfil these requirements. Catheterization is recommended to those individuals whose peripheral T exceeds 1.5 ng/ml. Such an aggressive approach seems warranted in view of the malignant potential of certain virilizing gonadal neoplasms, when non-invasive methods like ultrasound or computed tomography have failed. We believe that surgical exploration of an ovary is justified when a unilateral elevation of the OPG for T >2.7 ng/ml is detected. Similar guidelines regarding adrenal lesions cannot be provided because our catheterization experience with histologically proven adrenal neoplasms is nil. Still, such lesions are unlikely when peripheral T and DHAS levels are <1.5 ng/ml and <9000 ng/ml (Maroulis, 1981) respectively, and when a computed tomographic scan of the adrenals is negative. Unless a neoplasm is suspected, there are no clinical indications for catheterization. SUMMARY

The pathophysiology of glandular androgen hypersecretion must be regarded as a continuous process without sharp borderlines from normal to non-tumorous conditions, such as polycystic ovaries and hyperthecosis, to neoplastic disease. Hirsutism and related symptoms are most often caused by excess androgens of ovarian and/or adrenal origin, i.e. testosterone, dihydrotestosterone, A4-androstenedione, dehydroepiandrosterone and its sulphate. As demonstrated by selective catheterization of glandular effluents, combined hypersecretion occurs more frequently than either purely gonadal or adrenal overproduction. No correlation can be found between the type, frequency and extent of hormonal changes and the clinical, laparoscopic, angiographic, or histological findings. Dynamic function tests do not reliably discriminate between the various aetiological subgroups due to extremely variable and even non-specific individual responsiveness. Selective catheterization is presently the most sensitive method for the preoperative identification and localization of androgensecreting neoplasms.

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