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Adrenal and ovarian vein androgen levels and laparoscopic findings in hirsute women
laparoscopic findings in hirsute women GRETAJO NORTHROP, M.D., PH.D. JULIAN T. ARCHIE, M.D. SURESH K. PATEL, M.D. GEORGE D. WILBANKS, M.D. Chicago, Illinois Hirsute women pose a diagnostic dilemma when urinary 17-ketosteroid and serum testosterone levels are normal. To locate the site of androgen excess in 19 hirsute women, blood samples were collected from the left ovarian and adrenal veins via a catheter inserted into the right femoral vein. Laparoscopy and bilateral ovarian biopsies were also performed in 18 of the 19 patients studied. Nine women had elevated 17-ketosteroid (five patients) and/or antecubital serum testosterone (five patients) levels. Fourteen woman had elevated testosterone concentrations distributed as follows: ovarian vein (six), adrenal vein (one), adrenal and ovarian veins (seven). Androstenedione was elevated in the ovarian vein (seven) and both adrenal and ovarian veins (11) in 18 patients. Laparoscopic examination revealed that less than 50 per cent of the enlarged ovaries could be detected by pelvic examination. Histologic studies suggested that these patients comprised two groups: a group (six patients) who appeared to ovulate and a group (12 patients) who lacked evidence of ovulation.
H I R s u T I s M , like an iceberg, may be the only visible tip of widespread disease which is or will become manifest in the female patient. Too frequently the hirsute patient is released from the physician's office with the comforting diagnosis of constitutional or idopathic hirsutism, armed with the reassurance that nothing really serious is wrong. A thorough history and complete physical examination of the clinically hiruste patient frequently provide minimal diagnostic input. Extensive laboratory investigations are costly both in time and money
and offer minimal additional factual information requisite for prescribing specific treatment. Recent studies have shown that hirsute women have elevated metabolic clearance rates for androgens. 1 This confirms the clinical suspicion of androgen excess but permits the site of excess androgen production to remain elusive. The present study describes adrenal and ovarian vein testosterone and androstenedione levels in 19 clinically hirsute women. Laparoscopic findings and ovarian biopsy results are also reported in 18 of these patients. Materials and methods
From the Department of Medicine, Section of Endocrinology, and the Department of Obstetrics and Gynecology, and Section of Reproductive Endocrinology, Rush-Presbyterian-St. Luke's Medical Center. Presented at the Forty-second Annual Meeting of the Central Association of Obstetricans and Gynecologists, New Orleans, Louisiana, October 3-5, 1974.
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Reprint requests: Dr. Gretajo Northrop, Department of Medicine, Section of Endocrinology and
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ouowmg complete mswry ana pnystcat exammation, baseline 24 hour urine collections for 17hydroxy and 17-ketosteroids and pituitary gonadotropins were initiated. Blood was collected for 8 A.M. and 4 P.M. cortisol and protein-bound iodine ( PBI) as well as follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroxine (all detem1ined by radioimmunoassay methods\ . Skull roentgenograms were obtained and an intravenous pyelogram with tomograms was per·fomlCd T'O
.llush-Presbyteria.n-St. LukeJs
Medical Center, Chicago, Illinois.
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Androgen levels and laparoscopic findings in hirsute women
to evaluate adrenal size and assist with kidney location for greater ease in catheterization studies. Following percutaneous catheterization of the right femoral vein by the Seldinger technique, blood was collected from the lower part of the inferior vena cava ( IVC), the left ovarian vein ( LOv), and the left adrenal vein (LAv) for the radioimmunoassays of testosterone and androstenedione. Selective venography of the left adrenal and left ovary was also performed in most patients. A 2.0 mg. and 8.0 mg. dexamethasone suppression test with 24 hour urine collections for 17-hydroxy- and 17-ketosteroids made during the second day of each dose was also performed on 19 patients. 2 Eighteen of the patients also underwent laparoscopy and bilateral ovarian biopsy. Results
Quantitation of urinary 17-ketosteroid levels in 19 patients revealed only five women to have a 24 hour excretion above 12 mg., the upper limit of normal in our laboratory (Table I). No patient excreted more than 17.1 mg. per 24 hours. Baseline testosterone and androstenedione concentrations were determined in antecubital vein plasma. In 14 of the 19 hirsute women studied the testosterone levels were in the normal range; in 13 of these patients the plasma androstenedione level was also in the norn1al range (Table II). Four out of five of the women with elevated testosterone levels also had elevated androstenedione concentrations. Because the clinical sign, hirsutism, is frequently accompanied by normal urinary and peripheral plasma androgen levels, blood samples were obtained specifically from the ovarian and adrenal veins for analyses of testosterone and androstenedione in these 19 hirsute women. Fourteen women had elevated testosterone levels in one or both of the adrenal and ovarian veins (Table III). Six patients had elevated ovarian vein levels of testosterone and 7 women had elevated testosterone concentraiions in boih the ovarian and adrenal veins. Adrenal vein testosterone concentration was elevated in only a single woman. Androstenedione was elevated in 18 of the 19 women studied (Table III). This steroid was high in plasma obtained from both the adrenal and ovarian veins in 11 patients and was elevated only in the ovarian vein in seven patients. It is readily discovered from the data presented in Table III that androgen excess in adrenal and/or ovarian vein plasma corroborates the clinical find-
193
Table I. Baseline urinary 17 -ketosteroid excretion in 19 hirsute women I 7 -Ketosteroids (mg./24 hr.)
No. of patients
7 7
3-8 8-12 12-17.1 3-12
5 Female normal
Table II. Summary of baseline plasma androgen concentrations in 19 hirsute women Peripheral plasma androgen No. of hirsute women
Testosterone
Normal level Elevated level Female normal (ng./100 mi.)
14 5 20-54
Androstenedione
13 6 90-280
Table III. Distribution of androgen excess in ovarian and adrenal veins in 19 hirsute women No. of women with androgen excess* Androstenedione
Source of plasma
Testosterone
Left adrenal vein Left ovarian vein Both left adrenal vein and left ovarian vein Total
I 6 7
11
14
18
0 7
---------------------------------
*No difference in testosterone levels between antecubital and ovarian vein plasma was found in nonhirsute women. 3
ings of hirsutism in many more women than does androgen excess in peripheral plasma or urine (Tables I and II). Additional hormone evaluations in many of these patients were performed, i.e., urinary pituitary gonadotropins, plasma LH, by FSH, PBI, T-4 Murphy Pattee, and morning and afternoon cortisol levels. The concentrations were predominantly found to fall within the normal range in the majority of these women (Table IV). Inadequate diurnal variation, an afternoon cortisol concentration less than 50 per cent of the morning cortisol level, was present in 10 of the 16 women evaluated. Loss of diurnal variation in plasma cortisol in patients with Cushing's disease reflects hypothalamic disorder. A similar association in hirsute women has not been previously demonstrated.
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Table IV. Endrocrine profile in 19 hirsute women ---·--·
·-----
Patients
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Gonadotropins (Urinary mouse units)
FSH (Plasma MIU)
LH (Plasma MIU)
s. \'. R.R.
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R.S. A.R. C. H. L.A. M.H. N.H. C. D. K. w. C.R. S.R. E. S. D. S. c. L. S.D. Normal
6
7
6
5
6 6
6
T-4 (J.Lg/100 mi.)
5.5 6.4 5.2 4.8 5.6
7 7 5
17 14 21
6 9 10 6
13 19 13 9
12 9 9 5 2-50
21 17 38 26 5-100
+48 +24 +24 +24 + 6 +
6 13 9
PBI (J.Lg/100 ml.)
6
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6-48
9.2 4.8 5.2 5.8 7.6 6.7 6.1 6.4 6.7 6.9 3.4-7.4
1.3* 4.3 6.1 5.8 5.5 5.1 6.7 5.3 6.0 3-7
Cortisol plasmfl (J.Lg/100 ml..' -~~~,~
A.M.
P.M.
19.3 13.0 9.6 19.3 22.1 15.9 7.6 17.4 20.5
~·u ~
7
1.7
19.6 :2:U 16.H ti.7 ~lUi
16.~
25.7 23.8 6.3 25.6 11.8 35.2 22.7 27.1 35.0
l+.B
15.2 6.2 20.0 6.9 9.4 13.6 2-27
*Free thyroxine normal, 1-2.3 ng./100 mi.
Glucocorticoids are frequently used to treat hirsute women who are anovulatory, thus the classical dexamethasone suppression test was performed in these women. 2 If exct>ssive androgen is produced in the adrenal gland then suppression of this organ by exogenous glucocorticoid to lower pituitary release of ACTH (decrease adrenal stimulation) would be expected to be beneficial in properly selected patients. Only two of these 19 hirsute women snowea suppressiOn or unnary lt-Ketosterows even on the 8 mg. daily dose and only one of these two patients had elevated adrenal plasma androgen. To determine the effectiveness of bimanual pelvic 1
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expected in the polycystic ovary syndrome and in three patients the ovaries were histologically normal in spite of significantly elevated androgen levels present in the ovarian veins. In the other group of 12 patients ovarian pathology was documented by absence of evidence of ovulation and the presence of two or more of the following: decreased number of ova. thickened capsule, multiple c-ysts, and stromal hyperplasia or fibrosis.
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examination in detecting enlarged ovaries compari-
son was made with laparoscopic findings. Only 15 ovaries out of the 38 examined were judged to be enlarged by pelvic examinations whereas 33 0\'arie~ were enlarged by laparoscopic observations. Twentythree ovaries by pelvic examination and five ovaries by laparoscopy were recorded as normal in size. This confirms the reports by others of the difficulty in assessing ovarian size by pelvic examination." Ovarian biopsy was performed in 18 of these patients. The multiple pathologic findings can be summarized so that two specific groups are distinguished. One group of six patients had some evidence of the occurrence of ovluation, i.e ... presence
of a corpus luteum or corpus albicans. In three of these patients the ovarian capsule was thickened as
Comment
\Vomcn vvith hirsutisrn of recent onset deserve
careful consideration of their problems, as prevention is the only adequate assistance that can be offered. Once terminal hair growth is established the mam avenue of help for these women can only focus on preventing additional involvement of old areas as well as the initiation of new areas. The management of hirsutism, like many other medical problems. demands prompt investigation and appropriate treatment with an aim at early prevention. Laboratory studies are an indispensable part of the diagnostic workup of these patients. The timehonored urinary 17-ketosteroid evaluation has rnainly time and honor as its virtue and minimal diag· nostic importance because frequently the Yalues Inay be normal or even low normaL as seen m this study. Peripheral levels of plasma testosterone and
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Androgen ieveis and iaparoscopic findings rn hirsute women
androstenedione are good indicators, if elevated, that excessive androgen is being secreted. The localization of synthesis of these steroids, however, should be determined by sampling the efferent vessels of the ovary and adrenal via percutaneous femoral vein catheterization. This procedure may identify the source of androgen when peripheral levels are low. The procedure carries minimal morbidity and provides objective biochemical facts upon which to select optimal medical and/or surgical treatment. For example, glucocorticoid suppression therapy is most effective when adrenal androgen excess is present and ovarian wedge resection is usually curative in patients with ovarian androgen excess. A normal pelvic examination should not dissuade the physician from subsequent biochemical and histological studies as many patients with elevated androgen levels do not have enlarged ovaries when
l 95
evaluated by laparoscopy. 4 In addition, enlarged ovaries very frequently remain undetected, even in nonobese women, even when pelvic examination is performed by experienced gynecologists. This may be due to the fact that very large ovaries may move out of the pelvis and thus out of reach on bimanual examination. Thus laparoscopy remains an important part of the investigation of these patients because ovarian biopsy as well as a gross description of the ovary can be obtained. Characteristics of the capsule, size of the ovary, presence or absence of cysts, and sites of ovulation are but a few of the interesting facts obtainable at laparoscopy. Finally it may he concuded that idiopathic or constitutional hirsutism may be an atrogenic misdiagnosis and that adequate diagnostic evaluation will reveal the source of androgen excess and possibly provide a firm basis for treatment in most of these unhappy women.
REFERENCES
1. Kirschner, M. A., and Bardin, C. W.: Androgen pro-
duction and metabolism in normal and virilized women, Metabolism 21:667, 1972. 2. Liddle, G. W.: Tests of pituitary adrenal suppressibility in the diagnosis of Cushing's syndrome, J. Clin. Endocrinol. 20: 1539, 1960. 3. Stahl, N. L., Teeslink, C. R., Beauchamps, G., and
Discussion DR. JoHN H. MATTox, Omaha, Nebraska. Clinically significant hirsutism is currently thought to be determined by the availability of androgen and the sensitivity of the pilosebaceous apparatus. The significance of increased circulating androgens has received most emphasis whereas the role of the end organ has unfortunately been relegated to minor importance. There are overwhelming data confirming that the skin is an active endocrine organ in both the production and clearance of androgens, although the exact mechanism whereby the hair follicle responds has not been elucidated. I. 2 In the normal female, the net availability of free androgen can be thought to be the result of the production-ovarian secretion, adrenal secretion, and peripheral conversion-balanced by the rate of clearance-the plasma binding effect, the effect of hepatic clearance, and peripheral conversion.l· s-n The homeostatic control of androgen production is altered in the hirsute female and there has been poor correlation between isolated plasma androgen values or urinary androgen metabolite excretion deierminaiions and the clinical picture. Bardin and Lipsett' have found that the calculated testosterone production rates, the ratio between the product of the
Greenblatt, R. B.: Serum testosterone levels in hirsute women: A comparison of adrenal, ovarian and peripheral vein values, Obstet. Gynecol. 41: 650, 1973. 4. Kirschner, M. A., and Jacobs, J. B.: Combined ovarian and adrenal vein catheterization to determine the site(s) of androgen overproduction in hirsute women, J. Clin. Endocrinol. 33: 199, 1971.
metabolic clearance rate times the plasma concentration, are elevated in 95 per cent of women with hirsutism or polycystic ovary syndrome. 1 • 7 The operating premise of Northrop and associates is that in significant hirsutism androgen secretion will be elevated and that the source of this androgen can be localized by means of sampling the effluent of the ovaries and adrenals. The purpose of the present paper would seem in part to confirm the work published by Kirschner and Jacobs 8 and Rosenfield, Ehrlich, and Cleary, 9 in which the site of testosterone or androstenedione secretion is localized by transfemoral, adrenal, and ovarian vein catheter studies. Clinical description of the present author's 19 patients "'as absent, but ii is reasonable to assuine that there were accompanying problems such as obesity, infertility, menstrual abnormality, acne, or clitoral changes. Twenty-four hour urinary excretion, 17-ketosteroids, peripheral plasma androstenedione, and peripheral plasma testosterone levels were reported within the normal range for the majority of patients, which is consistent 'with previously recorded experience.. The crux of the paper deals with the experience of measuring testosterone and androstenedione in left ovarian and
]('ft adrenal vein samples, with adrenal vein androstenedinn being elevated more frequently than testosterone. It would have been helpful to know the specific values, their standard deviations, and whether the elevations were ~tatistically significant. Adrenal and ovarian venous androgens were elevated in at least 50 per cent of the patients. Kirschner and Jacobs 8 concluded from their rrport that only four of their 13 patients had combined ovarian and adrenal androgen excess, but they catheterized both adrenal and ovarian veins whenever possible. Sine<> adrenal and ovarian steroids are secreted episodically, single samples can easily fall at various times in relation to these bursts. It has been shown that adrenal vein dehydroepiandrosterone secretion varies in parallel '.vith adrenal vein cortisol secretion. 10 The authors could have concluded whether the androgen levels they found were caused by a concomitant sampling on top of such a burst. The apparent discrepancy in the data from Kirschner and Jacobs and Northrop and associates may be due to the fact that the latter group reported results from unilateral sampling technique. Even if one could be certain that the ovary or the adrenal were acting independently and that one or the other were solely responsible for androgen excess, the therapeutic response is still not predictable. In one study, in three out of nine patients, ovarian androgen production was suppressed with dexamethasone, suggesting some cross-linking between the control of adrenal and ovarian steroid secretion.' Judd and associates, 11 however, were able to localize the site of an ovarian neoplasm using the retrograde venous catheterization studies in a patient who demonstrated marked virilization and markedly elevated plasma testosterone. This technique could perhaps be of considerable value in the localization of androgen-producing tumors. The authors also reinforce the observation that in clinically significant hirsutism ovarian enlargement may or may not be palpable. Pelvic examinations are not without error in defining which ovaries are enlarged, particularly when one has the rather embarrassing opportunity of substantiating palpatory findings with pelvic endoscopy. Again, my preference would have been to have data regarding the specific measurements and the author's criteria for ovarian enlargement. The last point of this paper is most significant and is perhaps harder for most of us clinicians to accept. Neither the ovarian macroscopic nor microscopic picture consistently depicts or can necessarily be correlated with the biochemical aberration. It is always difficult to be certain that a biopsy sample is representative of true ovarian status. In summary, this has been a 1nost provocative paper which suggests that the routine use of adrenal and ovarian vein catheterization studies in blood sampling can be utilized in evaluation of our hirsute patients. It would be my contention that although our current clin-
ical and biochemical parameters are somewhar u•bati.,factory, this additional tool has some risk and dry·, not appear to offer enough of a diagnostic or thnapeutic advantage to warrant frequent usage. REFERENCES
1. Kirschner, M. A., and Bardin, C. W.: Metabolism 21: 667, 1972. 2. Thomas, J. P., and Oake, R. J.: J. C1in. Enduc-rinol. Metab. 38: 19, 1974. 3. Rosenfield, R. L.: J. Clin. Endocrinol. 32: 717, 1971. 4. Ismail, A. A. A., and Loraine, J. A.: Clin. Obstet. Gynecol. 12: 800, 1969. 5. Karp, L., and Herrmann, W. L.: Obstet. Gynecol. 41: 283, 1973. 6. Rosenfield, R. L., and Otto, P.: J. Clin. Endocrinol. 35: 818, 1972. 7. Bardin, C. W., and Lipsett, M. B.: J. Clin. Invest. 46: 891, 1967. 8. Kirschner, M. A.. , and Jacobs, J. B.: J. Clin. Endocrinol. 33: 199, 1971. 9. Rosenfield, R. L., Ehrlich, E. N., and Cleary, R. E.: ]. C lin. Endocrinol. 34: 71 7, 19 71. 10. Rosenfeld, R. S., Hellman, L., Roffwarg, H., Weitzman, E. D., Fukushima, D., and Gallagher, T. F.: J. Clin. Endocrinol. 33: 87, 1971. 11. Judd, H. L., Spore, W. W., Talner, L. B., Rigg, L. A., Yen, S. C., and Benirsch, K.: AM. J. 0BSTET. GYNECOL.120:92, 1974. DR. CARL J. LEVINSON, Houston, Texas. The authors are to be commended for their academic and complete approach to a most complicated and still confusing subject. In order to provide a base of information on which to discuss the paper, let me review with you some following bits of information: Androgenic steroids develop in the course of basic steroidogenesis by the ovary and adrenal. The delta-S pathway leads from pregnenolone to DHEA and androstenediol; the delta-4 pathway leads through progesterone, androstenedione, and testosterone. The androgenic properties of the 17 -ketosteroids are in doubt, but they undoubtedly play a significant role as precursors in the pathway toward the more potent androgens. The four compounds-androstenediol, testosterone, dihydrotestosteront>, and androstenediol-constitute the 17 -beta-hydroxy steroids and are the basic androgenic com pounds. 1 " The bulk of work performed in the last 1ll years is beginning to show a certain pattern upon which we may base some consideration. For example: in a discussion of testosterone/"· lu it would appear that less than half of the plasma testosterone is derived directly from the ovary and the adrenal. About half is derived from androstenedione and another 15 per cent from DHEA. In a normal female, oniy 1 per cent of the piasma testosterone is "free"-that is, not bound to TEBG or albumin. In the hirsute \Yoman, hov:ever, a different situation exists; a larger percentage of the hormone comes directly from the ovary and adrenal, much less from peripheral conversion, and the "free" testosterone is 3 to 4 per cent of the total."
Voiume 122
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Androgen levels and laparoscopic findings
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197
Comparable studies have been done on androstenedione in the normal female. Plasma androstenedione is derived in approximately equal quantities from the ovary and the adrenal; however, in the hirsute woman the amount coming from the ovary is significantly increased. (As we will note later, this has a direct relationship to clinical findings.) The mean plasma levels of testosterone, androstenedione, DHEA, and dihydrotestosterone are all about twice as high in hirsute women 1 - 3 but only half had elevated testosterone levels and elevated androstenedione levels. It is obvious, then, that the levels in any individual patient at any given moment may not be significant of the total picture. In the series of 19 patients presented, only five had elevated testosterone and only six had elevated androstenedione. In the literature, 10 · 15 • " a gradient difference is noted between the ovarian and adrenal vein levels and the plasma level. In the ovarian vein of a normal female, the androstenedione and testosterone levels are elevated over the plasma level. (This is at varience with the data from Stahl on three patients quoted by the authors.) Much the same situation exists in the hirsute woman, as supported by this paper. As for
terone. 9 • 17 Although the androgen levels I quoted before for most hirsute women are roughly double those of their nonhirsute sisters, these levels do not inhibit FSH/ LH production. Hirsute women ovulate, as did apparently one third of the patients in this series. The '"free" plasma testosterone measures out much the same in all hirsute women, whether the clinical picture is one of normal menses or one of an1enorrhea. A. t tin1es It 1s difficult to correlate the clinical picture to the specific findings; however, the concept is developing that it is androgen overproduction by the ovary that is more directly related to infertility. With the foregoing in mind, our authors have determined that, in their hirsute women, adrenal vein testosterone \vas elevated in eighi patients whereas adrenal vein androstenedione was elevated in 11 out of the 19 studied. Ovarian vein testosterone leVf~ls were elevated in 13 and androstenediol levels were elevated in 18. In both series it was the ovarian production that seemed to predominate. According to their own paper, the authors would then do a wedge resection, since they felt that this is "usually curative in patients with ovarian androgen excess." I suspect, however, that most of us might
the adrenal vein gradient, it is obvious that the number
use clon1iphene as an initial form of therapy. At this point, it might be of interest to inquire as to why clomid therapy works at all in the face of the excess ovarian
of patients who had elevated testosterone is similar in normal and hirsute patients. As regards androstenedione, although less than half the normal females show a gradient change, there is almost 100 per cent gradient elevation in hirsute women. Androgen is produced by the adrenal and the ovary·'· 11 as well as within some tissues. It is cleared by the liver and other extrahepatic tissues. Variable amounts come from the ovary and the adrenal but 50 per cent and more comes from peripheral conversion. One can think of clearance as a result of steroid binding to the plasma proteins and tissue metabolism; testosterone-estrogen-binding globulin and albumin bind approximat<>ly ~If) per cent of testosterone. Clearance is greater in hirsute women than in normal women and androgens seem to increase their own metabolism so that it is possible to have an increased production leading to increased metabolism and clearance which would not reflect itsplf in an apparently normal plasma testosterone level. The clinical and laboratory findings in hirsutism are often--but not always-related. The key seems to be the production of androgen which, at least in the case of testosterone, is increased in almost 100 per cent of the patients. The "free" plasma testosterone level is a good indicator, being elevated in 85 per cent, the plasma testosterone level is elevated in only half the patients, and the i 7-ketosteroids, our old standby of 10 years ago, are elevated in only 10 per cent. But even this information does not always help in an individual case. For example, hirsutism does not parallel the degree of elevation of "free" plasma testos-
androgen production. I am much less content with the correlation presented by laparoscopy. Our own institution was notorious in its inability to get competent observers to agree on the appearance and labeling of ovaries as seen through the laparoscope. Furthermore, Zographos and his co-workers20 in France concluded, as we must, that the gross appearance of the ovary does not permit a prejudgment of the functional value. Histologic evaluation is much more valuable. It would appear that we are beginning to open some doors but, alas, as we find new keys, they keep changing the locks. REFERENCES l j , E., ana ~_;naKmaicJtan, Z. H.: r1asma steroids in hirsutism, Obstet. Gynecol. 44: 171, 1974. 2. Abraham, G. E., and Chakmakjian, z. H.: Serum steroid levels during the menstrual cycle in a bilaterally adrenalectomized woman, J. Clin. Endocrinol. Metab. 37: 581, 1973. 3. Bardin, C. W., and Lipsett, M. B.: Testosterone and androstenedione blood production rates in normal women and women with idiopathic hirsutism or polycystic ovaries, J. Clin. Invest. 46: 891, 196 7. 4. Brooks, R. V.: Hirsutism and anovulatory infertility,
i. Abraham,
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5. Dupon, C., Rosenfield, R. L., and Cleary, R. E.: Sequential changes in total and free testosterone and androstenedione in plasma during spontaneous and clomid-induced ovulatory cycles, AM. J. OasTET. GYNECOL. 115: 4 78, 1973. 6. Judd, H. L., Scully, R. E., Herbst, A. L., Yen. S. S. C., Ingersok, F. M., and Kliman, B.: Familial hyperthecosis: Comparison of endocrinologic and
i 98
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histologic findings with polycystic ovarian disease, AM. J. 0BSTET. GYNECOL. 117: 976, 1973. Farber, M., Daoust, P. R., and Rogers, J.: Hyperthecosis syndrome, Obstet. Gynecol. 44: 35, 1974. Kapen, S., Boyar, R., Hellman, L., and Weitzman, E. D.: Episodic release of luteinizing hormone at mid-menstrual cycle in normal adult women, ]. Clin. Endocrinol. Metab. 36: 724, 1973. Karp, L., and Herrman, W. L.: Diagnosis and treatment of hirsutism in women, Obstet. Gynecol. 41: 283, 1973. Kirschner, M. A., and Jacobs, J. B.: Combined ovarian and adrenal vein catheterization to determine the site ( s) of androgen overproduction in hirsute women, ]. Clin. Endocrinol. 33: 199, 1971. Kirschner, ~"{ . .~.AJ..., and Bardin, C. \A/.: "A,.,ndrogen production and metabolism in normal and virilized women, Progr. Endocrinol. Metab. 21: 667, 1972. v:~
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Loriaux, L., and Nieschlag, E.: The production, origin and role of dehydraepiandrosterone and A 5 androstenediol as androgen prehormones in hirsute women, ]. Clin. Endocrinol. Metab. 37: 183, 1973. Mahoudeau, J. A., Bardin, C. W., and Lipsett, M. B.: The metabolic clearance rate and origin of plasma dihydrotestosterone in man and its conversion to the 5a-androstanediols, J. Clin. Invest. 50: 1338, 1971. Greenblatt, R. B., and Stahl, N. L.: Constitutional hirsutism: Endocrinopathy or genetic curse, .T. Reprod. Med. 11:96, 1973. Rosenfield, R. L., Ehrlich, E. N., and Cleary, R. E.: Adrenal and ovarian contributions to the elevated free plasma androgen levels in hirsute women, J. Clin. Endocrinol. 34: 92, 1972. Rosenfield, R. L.: Plasma testosterone binding globulin and indexes of the concentration of unbound plasma androgens in normal and hirsute subjects, J. Clin. Endocrinol. 32: 717, 1971. Rosenfield, R. L.: Relationship of androgens to female hirsutism and infertility, ]. Reprod. Med. 11: 87, 1973. Stahl, N. L., Teesling, C. R., and Greenblatt, R. B.: Ovarian, adrenal, and peripheral testosterone levels in the polycystic ovary syndrome, AM. J. OasTET. GYNECOL. 117: 194, 1973. Stahl, N. L., Teeslink, C. R., Beauchamps, G., and Greenblatt, R. B.: Serum testosterone levels in hir-
sute women: A comparison of adrenal. ovariau and peripheral vein values, Obstet. Gyne··· ,J. 41: 65•). 1973. 20. Zographos, G., Zakarian, S., Bergier, G., a!lu \· art>treDauvergne, Y.: Problems in the into'rpretation crf oviran biopsies in functional gynecolol(ic di;orders and sterility of ovarian origin, ]. Reprocl. ~IecL 10: 295, 1973.
DR. NoRTHROP (Closing). The present stag<· r.J management of hirsute patients is certainly inadequate, primarily because of failure in diagnosis of the site of excessive androgen production. It has been reported by D1. tvfaroulis working in Dr. ;\.braharn \ laboratory that chorionic gonadotropin, which is predominantly LH, stimulates the adrenal gland. We have recently found that ACTH stimulates the ovary in some patients. Thus prolonged and elaborated urine collections afta various stimulation or suppression manipulations with drugs would se('m in theory, and do reflect clinically, poor diagnostic procedures. A~hhough it is perhaps too eady to evaluate the final clinical usefulness of ovarian and adrPnal vein catheterization, this technique appears to offer an approach to diagnosis which should providt' insight into appropriate selection of treatment for thPs<' unhappy womt>n. The level of estrogen present is also an important factor brcau~t~ it influences the ainount nf binding of testosterone. Only free testosterone is active physiologically, thus the total testosterone levels which we now 111easure may not reflect the physiologic effect. In addition, progesterone may displace testosterone from thc· binding; protein so there are ntany factor:-. which n1ay account for the varied clinical effects of a given testosterone level in any given patient. In conclusion, in order to manage these patients at this time, we must determine the sight of excessivt' androgen production in the clinically hirsute woman and then direct our treatment toward normalizing the androgen lPvt~l arising frorn the sight.
H I R s u T I s M , like an iceberg, may be the only visible tip of widespread disease which is or will become manifest in the female patient. Too frequently the hirsute patient is released from the physician's office with the comforting diagnosis of constitutional or idopathic hirsutism, armed with the reassurance that nothing really serious is wrong. A thorough history and complete physical examination of the clinically hiruste patient frequently provide minimal diagnostic input. Extensive laboratory investigations are costly both in time and money
and offer minimal additional factual information requisite for prescribing specific treatment. Recent studies have shown that hirsute women have elevated metabolic clearance rates for androgens. 1 This confirms the clinical suspicion of androgen excess but permits the site of excess androgen production to remain elusive. The present study describes adrenal and ovarian vein testosterone and androstenedione levels in 19 clinically hirsute women. Laparoscopic findings and ovarian biopsy results are also reported in 18 of these patients. Materials and methods
From the Department of Medicine, Section of Endocrinology, and the Department of Obstetrics and Gynecology, and Section of Reproductive Endocrinology, Rush-Presbyterian-St. Luke's Medical Center. Presented at the Forty-second Annual Meeting of the Central Association of Obstetricans and Gynecologists, New Orleans, Louisiana, October 3-5, 1974.
1'
Reprint requests: Dr. Gretajo Northrop, Department of Medicine, Section of Endocrinology and
~"-1 etabolismJ
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1
•
1
.
1
•
•
1
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•
- 1
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-
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ouowmg complete mswry ana pnystcat exammation, baseline 24 hour urine collections for 17hydroxy and 17-ketosteroids and pituitary gonadotropins were initiated. Blood was collected for 8 A.M. and 4 P.M. cortisol and protein-bound iodine ( PBI) as well as follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroxine (all detem1ined by radioimmunoassay methods\ . Skull roentgenograms were obtained and an intravenous pyelogram with tomograms was per·fomlCd T'O
.llush-Presbyteria.n-St. LukeJs
Medical Center, Chicago, Illinois.
192
Volume 122 Number 2
Androgen levels and laparoscopic findings in hirsute women
to evaluate adrenal size and assist with kidney location for greater ease in catheterization studies. Following percutaneous catheterization of the right femoral vein by the Seldinger technique, blood was collected from the lower part of the inferior vena cava ( IVC), the left ovarian vein ( LOv), and the left adrenal vein (LAv) for the radioimmunoassays of testosterone and androstenedione. Selective venography of the left adrenal and left ovary was also performed in most patients. A 2.0 mg. and 8.0 mg. dexamethasone suppression test with 24 hour urine collections for 17-hydroxy- and 17-ketosteroids made during the second day of each dose was also performed on 19 patients. 2 Eighteen of the patients also underwent laparoscopy and bilateral ovarian biopsy. Results
Quantitation of urinary 17-ketosteroid levels in 19 patients revealed only five women to have a 24 hour excretion above 12 mg., the upper limit of normal in our laboratory (Table I). No patient excreted more than 17.1 mg. per 24 hours. Baseline testosterone and androstenedione concentrations were determined in antecubital vein plasma. In 14 of the 19 hirsute women studied the testosterone levels were in the normal range; in 13 of these patients the plasma androstenedione level was also in the norn1al range (Table II). Four out of five of the women with elevated testosterone levels also had elevated androstenedione concentrations. Because the clinical sign, hirsutism, is frequently accompanied by normal urinary and peripheral plasma androgen levels, blood samples were obtained specifically from the ovarian and adrenal veins for analyses of testosterone and androstenedione in these 19 hirsute women. Fourteen women had elevated testosterone levels in one or both of the adrenal and ovarian veins (Table III). Six patients had elevated ovarian vein levels of testosterone and 7 women had elevated testosterone concentraiions in boih the ovarian and adrenal veins. Adrenal vein testosterone concentration was elevated in only a single woman. Androstenedione was elevated in 18 of the 19 women studied (Table III). This steroid was high in plasma obtained from both the adrenal and ovarian veins in 11 patients and was elevated only in the ovarian vein in seven patients. It is readily discovered from the data presented in Table III that androgen excess in adrenal and/or ovarian vein plasma corroborates the clinical find-
193
Table I. Baseline urinary 17 -ketosteroid excretion in 19 hirsute women I 7 -Ketosteroids (mg./24 hr.)
No. of patients
7 7
3-8 8-12 12-17.1 3-12
5 Female normal
Table II. Summary of baseline plasma androgen concentrations in 19 hirsute women Peripheral plasma androgen No. of hirsute women
Testosterone
Normal level Elevated level Female normal (ng./100 mi.)
14 5 20-54
Androstenedione
13 6 90-280
Table III. Distribution of androgen excess in ovarian and adrenal veins in 19 hirsute women No. of women with androgen excess* Androstenedione
Source of plasma
Testosterone
Left adrenal vein Left ovarian vein Both left adrenal vein and left ovarian vein Total
I 6 7
11
14
18
0 7
---------------------------------
*No difference in testosterone levels between antecubital and ovarian vein plasma was found in nonhirsute women. 3
ings of hirsutism in many more women than does androgen excess in peripheral plasma or urine (Tables I and II). Additional hormone evaluations in many of these patients were performed, i.e., urinary pituitary gonadotropins, plasma LH, by FSH, PBI, T-4 Murphy Pattee, and morning and afternoon cortisol levels. The concentrations were predominantly found to fall within the normal range in the majority of these women (Table IV). Inadequate diurnal variation, an afternoon cortisol concentration less than 50 per cent of the morning cortisol level, was present in 10 of the 16 women evaluated. Loss of diurnal variation in plasma cortisol in patients with Cushing's disease reflects hypothalamic disorder. A similar association in hirsute women has not been previously demonstrated.
Am.]. Ohslt . ( 'lll'('•l
Table IV. Endrocrine profile in 19 hirsute women ---·--·
·-----
Patients
~----..,.--------
Gonadotropins (Urinary mouse units)
FSH (Plasma MIU)
LH (Plasma MIU)
s. \'. R.R.
+ + + +
N. K. A.M. Y.M.
R.S. A.R. C. H. L.A. M.H. N.H. C. D. K. w. C.R. S.R. E. S. D. S. c. L. S.D. Normal
6
7
6
5
6 6
6
T-4 (J.Lg/100 mi.)
5.5 6.4 5.2 4.8 5.6
7 7 5
17 14 21
6 9 10 6
13 19 13 9
12 9 9 5 2-50
21 17 38 26 5-100
+48 +24 +24 +24 + 6 +
6 13 9
PBI (J.Lg/100 ml.)
6
+24-
6-48
9.2 4.8 5.2 5.8 7.6 6.7 6.1 6.4 6.7 6.9 3.4-7.4
1.3* 4.3 6.1 5.8 5.5 5.1 6.7 5.3 6.0 3-7
Cortisol plasmfl (J.Lg/100 ml..' -~~~,~
A.M.
P.M.
19.3 13.0 9.6 19.3 22.1 15.9 7.6 17.4 20.5
~·u ~
7
1.7
19.6 :2:U 16.H ti.7 ~lUi
16.~
25.7 23.8 6.3 25.6 11.8 35.2 22.7 27.1 35.0
l+.B
15.2 6.2 20.0 6.9 9.4 13.6 2-27
*Free thyroxine normal, 1-2.3 ng./100 mi.
Glucocorticoids are frequently used to treat hirsute women who are anovulatory, thus the classical dexamethasone suppression test was performed in these women. 2 If exct>ssive androgen is produced in the adrenal gland then suppression of this organ by exogenous glucocorticoid to lower pituitary release of ACTH (decrease adrenal stimulation) would be expected to be beneficial in properly selected patients. Only two of these 19 hirsute women snowea suppressiOn or unnary lt-Ketosterows even on the 8 mg. daily dose and only one of these two patients had elevated adrenal plasma androgen. To determine the effectiveness of bimanual pelvic 1
1
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expected in the polycystic ovary syndrome and in three patients the ovaries were histologically normal in spite of significantly elevated androgen levels present in the ovarian veins. In the other group of 12 patients ovarian pathology was documented by absence of evidence of ovulation and the presence of two or more of the following: decreased number of ova. thickened capsule, multiple c-ysts, and stromal hyperplasia or fibrosis.
"1
examination in detecting enlarged ovaries compari-
son was made with laparoscopic findings. Only 15 ovaries out of the 38 examined were judged to be enlarged by pelvic examinations whereas 33 0\'arie~ were enlarged by laparoscopic observations. Twentythree ovaries by pelvic examination and five ovaries by laparoscopy were recorded as normal in size. This confirms the reports by others of the difficulty in assessing ovarian size by pelvic examination." Ovarian biopsy was performed in 18 of these patients. The multiple pathologic findings can be summarized so that two specific groups are distinguished. One group of six patients had some evidence of the occurrence of ovluation, i.e ... presence
of a corpus luteum or corpus albicans. In three of these patients the ovarian capsule was thickened as
Comment
\Vomcn vvith hirsutisrn of recent onset deserve
careful consideration of their problems, as prevention is the only adequate assistance that can be offered. Once terminal hair growth is established the mam avenue of help for these women can only focus on preventing additional involvement of old areas as well as the initiation of new areas. The management of hirsutism, like many other medical problems. demands prompt investigation and appropriate treatment with an aim at early prevention. Laboratory studies are an indispensable part of the diagnostic workup of these patients. The timehonored urinary 17-ketosteroid evaluation has rnainly time and honor as its virtue and minimal diag· nostic importance because frequently the Yalues Inay be normal or even low normaL as seen m this study. Peripheral levels of plasma testosterone and
Voiume 122 Number 2
Androgen ieveis and iaparoscopic findings rn hirsute women
androstenedione are good indicators, if elevated, that excessive androgen is being secreted. The localization of synthesis of these steroids, however, should be determined by sampling the efferent vessels of the ovary and adrenal via percutaneous femoral vein catheterization. This procedure may identify the source of androgen when peripheral levels are low. The procedure carries minimal morbidity and provides objective biochemical facts upon which to select optimal medical and/or surgical treatment. For example, glucocorticoid suppression therapy is most effective when adrenal androgen excess is present and ovarian wedge resection is usually curative in patients with ovarian androgen excess. A normal pelvic examination should not dissuade the physician from subsequent biochemical and histological studies as many patients with elevated androgen levels do not have enlarged ovaries when
l 95
evaluated by laparoscopy. 4 In addition, enlarged ovaries very frequently remain undetected, even in nonobese women, even when pelvic examination is performed by experienced gynecologists. This may be due to the fact that very large ovaries may move out of the pelvis and thus out of reach on bimanual examination. Thus laparoscopy remains an important part of the investigation of these patients because ovarian biopsy as well as a gross description of the ovary can be obtained. Characteristics of the capsule, size of the ovary, presence or absence of cysts, and sites of ovulation are but a few of the interesting facts obtainable at laparoscopy. Finally it may he concuded that idiopathic or constitutional hirsutism may be an atrogenic misdiagnosis and that adequate diagnostic evaluation will reveal the source of androgen excess and possibly provide a firm basis for treatment in most of these unhappy women.
REFERENCES
1. Kirschner, M. A., and Bardin, C. W.: Androgen pro-
duction and metabolism in normal and virilized women, Metabolism 21:667, 1972. 2. Liddle, G. W.: Tests of pituitary adrenal suppressibility in the diagnosis of Cushing's syndrome, J. Clin. Endocrinol. 20: 1539, 1960. 3. Stahl, N. L., Teeslink, C. R., Beauchamps, G., and
Discussion DR. JoHN H. MATTox, Omaha, Nebraska. Clinically significant hirsutism is currently thought to be determined by the availability of androgen and the sensitivity of the pilosebaceous apparatus. The significance of increased circulating androgens has received most emphasis whereas the role of the end organ has unfortunately been relegated to minor importance. There are overwhelming data confirming that the skin is an active endocrine organ in both the production and clearance of androgens, although the exact mechanism whereby the hair follicle responds has not been elucidated. I. 2 In the normal female, the net availability of free androgen can be thought to be the result of the production-ovarian secretion, adrenal secretion, and peripheral conversion-balanced by the rate of clearance-the plasma binding effect, the effect of hepatic clearance, and peripheral conversion.l· s-n The homeostatic control of androgen production is altered in the hirsute female and there has been poor correlation between isolated plasma androgen values or urinary androgen metabolite excretion deierminaiions and the clinical picture. Bardin and Lipsett' have found that the calculated testosterone production rates, the ratio between the product of the
Greenblatt, R. B.: Serum testosterone levels in hirsute women: A comparison of adrenal, ovarian and peripheral vein values, Obstet. Gynecol. 41: 650, 1973. 4. Kirschner, M. A., and Jacobs, J. B.: Combined ovarian and adrenal vein catheterization to determine the site(s) of androgen overproduction in hirsute women, J. Clin. Endocrinol. 33: 199, 1971.
metabolic clearance rate times the plasma concentration, are elevated in 95 per cent of women with hirsutism or polycystic ovary syndrome. 1 • 7 The operating premise of Northrop and associates is that in significant hirsutism androgen secretion will be elevated and that the source of this androgen can be localized by means of sampling the effluent of the ovaries and adrenals. The purpose of the present paper would seem in part to confirm the work published by Kirschner and Jacobs 8 and Rosenfield, Ehrlich, and Cleary, 9 in which the site of testosterone or androstenedione secretion is localized by transfemoral, adrenal, and ovarian vein catheter studies. Clinical description of the present author's 19 patients "'as absent, but ii is reasonable to assuine that there were accompanying problems such as obesity, infertility, menstrual abnormality, acne, or clitoral changes. Twenty-four hour urinary excretion, 17-ketosteroids, peripheral plasma androstenedione, and peripheral plasma testosterone levels were reported within the normal range for the majority of patients, which is consistent 'with previously recorded experience.. The crux of the paper deals with the experience of measuring testosterone and androstenedione in left ovarian and
]('ft adrenal vein samples, with adrenal vein androstenedinn being elevated more frequently than testosterone. It would have been helpful to know the specific values, their standard deviations, and whether the elevations were ~tatistically significant. Adrenal and ovarian venous androgens were elevated in at least 50 per cent of the patients. Kirschner and Jacobs 8 concluded from their rrport that only four of their 13 patients had combined ovarian and adrenal androgen excess, but they catheterized both adrenal and ovarian veins whenever possible. Sine<> adrenal and ovarian steroids are secreted episodically, single samples can easily fall at various times in relation to these bursts. It has been shown that adrenal vein dehydroepiandrosterone secretion varies in parallel '.vith adrenal vein cortisol secretion. 10 The authors could have concluded whether the androgen levels they found were caused by a concomitant sampling on top of such a burst. The apparent discrepancy in the data from Kirschner and Jacobs and Northrop and associates may be due to the fact that the latter group reported results from unilateral sampling technique. Even if one could be certain that the ovary or the adrenal were acting independently and that one or the other were solely responsible for androgen excess, the therapeutic response is still not predictable. In one study, in three out of nine patients, ovarian androgen production was suppressed with dexamethasone, suggesting some cross-linking between the control of adrenal and ovarian steroid secretion.' Judd and associates, 11 however, were able to localize the site of an ovarian neoplasm using the retrograde venous catheterization studies in a patient who demonstrated marked virilization and markedly elevated plasma testosterone. This technique could perhaps be of considerable value in the localization of androgen-producing tumors. The authors also reinforce the observation that in clinically significant hirsutism ovarian enlargement may or may not be palpable. Pelvic examinations are not without error in defining which ovaries are enlarged, particularly when one has the rather embarrassing opportunity of substantiating palpatory findings with pelvic endoscopy. Again, my preference would have been to have data regarding the specific measurements and the author's criteria for ovarian enlargement. The last point of this paper is most significant and is perhaps harder for most of us clinicians to accept. Neither the ovarian macroscopic nor microscopic picture consistently depicts or can necessarily be correlated with the biochemical aberration. It is always difficult to be certain that a biopsy sample is representative of true ovarian status. In summary, this has been a 1nost provocative paper which suggests that the routine use of adrenal and ovarian vein catheterization studies in blood sampling can be utilized in evaluation of our hirsute patients. It would be my contention that although our current clin-
ical and biochemical parameters are somewhar u•bati.,factory, this additional tool has some risk and dry·, not appear to offer enough of a diagnostic or thnapeutic advantage to warrant frequent usage. REFERENCES
1. Kirschner, M. A., and Bardin, C. W.: Metabolism 21: 667, 1972. 2. Thomas, J. P., and Oake, R. J.: J. C1in. Enduc-rinol. Metab. 38: 19, 1974. 3. Rosenfield, R. L.: J. Clin. Endocrinol. 32: 717, 1971. 4. Ismail, A. A. A., and Loraine, J. A.: Clin. Obstet. Gynecol. 12: 800, 1969. 5. Karp, L., and Herrmann, W. L.: Obstet. Gynecol. 41: 283, 1973. 6. Rosenfield, R. L., and Otto, P.: J. Clin. Endocrinol. 35: 818, 1972. 7. Bardin, C. W., and Lipsett, M. B.: J. Clin. Invest. 46: 891, 1967. 8. Kirschner, M. A.. , and Jacobs, J. B.: J. Clin. Endocrinol. 33: 199, 1971. 9. Rosenfield, R. L., Ehrlich, E. N., and Cleary, R. E.: ]. C lin. Endocrinol. 34: 71 7, 19 71. 10. Rosenfeld, R. S., Hellman, L., Roffwarg, H., Weitzman, E. D., Fukushima, D., and Gallagher, T. F.: J. Clin. Endocrinol. 33: 87, 1971. 11. Judd, H. L., Spore, W. W., Talner, L. B., Rigg, L. A., Yen, S. C., and Benirsch, K.: AM. J. 0BSTET. GYNECOL.120:92, 1974. DR. CARL J. LEVINSON, Houston, Texas. The authors are to be commended for their academic and complete approach to a most complicated and still confusing subject. In order to provide a base of information on which to discuss the paper, let me review with you some following bits of information: Androgenic steroids develop in the course of basic steroidogenesis by the ovary and adrenal. The delta-S pathway leads from pregnenolone to DHEA and androstenediol; the delta-4 pathway leads through progesterone, androstenedione, and testosterone. The androgenic properties of the 17 -ketosteroids are in doubt, but they undoubtedly play a significant role as precursors in the pathway toward the more potent androgens. The four compounds-androstenediol, testosterone, dihydrotestosteront>, and androstenediol-constitute the 17 -beta-hydroxy steroids and are the basic androgenic com pounds. 1 " The bulk of work performed in the last 1ll years is beginning to show a certain pattern upon which we may base some consideration. For example: in a discussion of testosterone/"· lu it would appear that less than half of the plasma testosterone is derived directly from the ovary and the adrenal. About half is derived from androstenedione and another 15 per cent from DHEA. In a normal female, oniy 1 per cent of the piasma testosterone is "free"-that is, not bound to TEBG or albumin. In the hirsute \Yoman, hov:ever, a different situation exists; a larger percentage of the hormone comes directly from the ovary and adrenal, much less from peripheral conversion, and the "free" testosterone is 3 to 4 per cent of the total."
Voiume 122
N"uml>t'r 2
Androgen levels and laparoscopic findings
tn
hirsute women
197
Comparable studies have been done on androstenedione in the normal female. Plasma androstenedione is derived in approximately equal quantities from the ovary and the adrenal; however, in the hirsute woman the amount coming from the ovary is significantly increased. (As we will note later, this has a direct relationship to clinical findings.) The mean plasma levels of testosterone, androstenedione, DHEA, and dihydrotestosterone are all about twice as high in hirsute women 1 - 3 but only half had elevated testosterone levels and elevated androstenedione levels. It is obvious, then, that the levels in any individual patient at any given moment may not be significant of the total picture. In the series of 19 patients presented, only five had elevated testosterone and only six had elevated androstenedione. In the literature, 10 · 15 • " a gradient difference is noted between the ovarian and adrenal vein levels and the plasma level. In the ovarian vein of a normal female, the androstenedione and testosterone levels are elevated over the plasma level. (This is at varience with the data from Stahl on three patients quoted by the authors.) Much the same situation exists in the hirsute woman, as supported by this paper. As for
terone. 9 • 17 Although the androgen levels I quoted before for most hirsute women are roughly double those of their nonhirsute sisters, these levels do not inhibit FSH/ LH production. Hirsute women ovulate, as did apparently one third of the patients in this series. The '"free" plasma testosterone measures out much the same in all hirsute women, whether the clinical picture is one of normal menses or one of an1enorrhea. A. t tin1es It 1s difficult to correlate the clinical picture to the specific findings; however, the concept is developing that it is androgen overproduction by the ovary that is more directly related to infertility. With the foregoing in mind, our authors have determined that, in their hirsute women, adrenal vein testosterone \vas elevated in eighi patients whereas adrenal vein androstenedione was elevated in 11 out of the 19 studied. Ovarian vein testosterone leVf~ls were elevated in 13 and androstenediol levels were elevated in 18. In both series it was the ovarian production that seemed to predominate. According to their own paper, the authors would then do a wedge resection, since they felt that this is "usually curative in patients with ovarian androgen excess." I suspect, however, that most of us might
the adrenal vein gradient, it is obvious that the number
use clon1iphene as an initial form of therapy. At this point, it might be of interest to inquire as to why clomid therapy works at all in the face of the excess ovarian
of patients who had elevated testosterone is similar in normal and hirsute patients. As regards androstenedione, although less than half the normal females show a gradient change, there is almost 100 per cent gradient elevation in hirsute women. Androgen is produced by the adrenal and the ovary·'· 11 as well as within some tissues. It is cleared by the liver and other extrahepatic tissues. Variable amounts come from the ovary and the adrenal but 50 per cent and more comes from peripheral conversion. One can think of clearance as a result of steroid binding to the plasma proteins and tissue metabolism; testosterone-estrogen-binding globulin and albumin bind approximat<>ly ~If) per cent of testosterone. Clearance is greater in hirsute women than in normal women and androgens seem to increase their own metabolism so that it is possible to have an increased production leading to increased metabolism and clearance which would not reflect itsplf in an apparently normal plasma testosterone level. The clinical and laboratory findings in hirsutism are often--but not always-related. The key seems to be the production of androgen which, at least in the case of testosterone, is increased in almost 100 per cent of the patients. The "free" plasma testosterone level is a good indicator, being elevated in 85 per cent, the plasma testosterone level is elevated in only half the patients, and the i 7-ketosteroids, our old standby of 10 years ago, are elevated in only 10 per cent. But even this information does not always help in an individual case. For example, hirsutism does not parallel the degree of elevation of "free" plasma testos-
androgen production. I am much less content with the correlation presented by laparoscopy. Our own institution was notorious in its inability to get competent observers to agree on the appearance and labeling of ovaries as seen through the laparoscope. Furthermore, Zographos and his co-workers20 in France concluded, as we must, that the gross appearance of the ovary does not permit a prejudgment of the functional value. Histologic evaluation is much more valuable. It would appear that we are beginning to open some doors but, alas, as we find new keys, they keep changing the locks. REFERENCES l j , E., ana ~_;naKmaicJtan, Z. H.: r1asma steroids in hirsutism, Obstet. Gynecol. 44: 171, 1974. 2. Abraham, G. E., and Chakmakjian, z. H.: Serum steroid levels during the menstrual cycle in a bilaterally adrenalectomized woman, J. Clin. Endocrinol. Metab. 37: 581, 1973. 3. Bardin, C. W., and Lipsett, M. B.: Testosterone and androstenedione blood production rates in normal women and women with idiopathic hirsutism or polycystic ovaries, J. Clin. Invest. 46: 891, 196 7. 4. Brooks, R. V.: Hirsutism and anovulatory infertility,
i. Abraham,
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5. Dupon, C., Rosenfield, R. L., and Cleary, R. E.: Sequential changes in total and free testosterone and androstenedione in plasma during spontaneous and clomid-induced ovulatory cycles, AM. J. OasTET. GYNECOL. 115: 4 78, 1973. 6. Judd, H. L., Scully, R. E., Herbst, A. L., Yen. S. S. C., Ingersok, F. M., and Kliman, B.: Familial hyperthecosis: Comparison of endocrinologic and
i 98
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16.
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histologic findings with polycystic ovarian disease, AM. J. 0BSTET. GYNECOL. 117: 976, 1973. Farber, M., Daoust, P. R., and Rogers, J.: Hyperthecosis syndrome, Obstet. Gynecol. 44: 35, 1974. Kapen, S., Boyar, R., Hellman, L., and Weitzman, E. D.: Episodic release of luteinizing hormone at mid-menstrual cycle in normal adult women, ]. Clin. Endocrinol. Metab. 36: 724, 1973. Karp, L., and Herrman, W. L.: Diagnosis and treatment of hirsutism in women, Obstet. Gynecol. 41: 283, 1973. Kirschner, M. A., and Jacobs, J. B.: Combined ovarian and adrenal vein catheterization to determine the site ( s) of androgen overproduction in hirsute women, ]. Clin. Endocrinol. 33: 199, 1971. Kirschner, ~"{ . .~.AJ..., and Bardin, C. \A/.: "A,.,ndrogen production and metabolism in normal and virilized women, Progr. Endocrinol. Metab. 21: 667, 1972. v:~
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Loriaux, L., and Nieschlag, E.: The production, origin and role of dehydraepiandrosterone and A 5 androstenediol as androgen prehormones in hirsute women, ]. Clin. Endocrinol. Metab. 37: 183, 1973. Mahoudeau, J. A., Bardin, C. W., and Lipsett, M. B.: The metabolic clearance rate and origin of plasma dihydrotestosterone in man and its conversion to the 5a-androstanediols, J. Clin. Invest. 50: 1338, 1971. Greenblatt, R. B., and Stahl, N. L.: Constitutional hirsutism: Endocrinopathy or genetic curse, .T. Reprod. Med. 11:96, 1973. Rosenfield, R. L., Ehrlich, E. N., and Cleary, R. E.: Adrenal and ovarian contributions to the elevated free plasma androgen levels in hirsute women, J. Clin. Endocrinol. 34: 92, 1972. Rosenfield, R. L.: Plasma testosterone binding globulin and indexes of the concentration of unbound plasma androgens in normal and hirsute subjects, J. Clin. Endocrinol. 32: 717, 1971. Rosenfield, R. L.: Relationship of androgens to female hirsutism and infertility, ]. Reprod. Med. 11: 87, 1973. Stahl, N. L., Teesling, C. R., and Greenblatt, R. B.: Ovarian, adrenal, and peripheral testosterone levels in the polycystic ovary syndrome, AM. J. OasTET. GYNECOL. 117: 194, 1973. Stahl, N. L., Teeslink, C. R., Beauchamps, G., and Greenblatt, R. B.: Serum testosterone levels in hir-
sute women: A comparison of adrenal. ovariau and peripheral vein values, Obstet. Gyne··· ,J. 41: 65•). 1973. 20. Zographos, G., Zakarian, S., Bergier, G., a!lu \· art>treDauvergne, Y.: Problems in the into'rpretation crf oviran biopsies in functional gynecolol(ic di;orders and sterility of ovarian origin, ]. Reprocl. ~IecL 10: 295, 1973.
DR. NoRTHROP (Closing). The present stag<· r.J management of hirsute patients is certainly inadequate, primarily because of failure in diagnosis of the site of excessive androgen production. It has been reported by D1. tvfaroulis working in Dr. ;\.braharn \ laboratory that chorionic gonadotropin, which is predominantly LH, stimulates the adrenal gland. We have recently found that ACTH stimulates the ovary in some patients. Thus prolonged and elaborated urine collections afta various stimulation or suppression manipulations with drugs would se('m in theory, and do reflect clinically, poor diagnostic procedures. A~hhough it is perhaps too eady to evaluate the final clinical usefulness of ovarian and adrPnal vein catheterization, this technique appears to offer an approach to diagnosis which should providt' insight into appropriate selection of treatment for thPs<' unhappy womt>n. The level of estrogen present is also an important factor brcau~t~ it influences the ainount nf binding of testosterone. Only free testosterone is active physiologically, thus the total testosterone levels which we now 111easure may not reflect the physiologic effect. In addition, progesterone may displace testosterone from thc· binding; protein so there are ntany factor:-. which n1ay account for the varied clinical effects of a given testosterone level in any given patient. In conclusion, in order to manage these patients at this time, we must determine the sight of excessivt' androgen production in the clinically hirsute woman and then direct our treatment toward normalizing the androgen lPvt~l arising frorn the sight.