COMMENTS

4. 5. 6.

7. 8. 9. 10.

In Pasteels, J. L., and C. Robyn (eds.), Human Prolactin, Int. Congr. Ser. No. 308, Excerpta Medica, Amsterdam, 1973, p. 98. Parker, D. C , L. G. Rossman, and E. F. Vanderl a a n j Clin Endocrinol Metab 36: 1119, 1973. Ehara, Y., T. Siler, G. Vandenberg, Y. N. Sinha, and S. S. C. Yen, Am J Obstet Gynecol 117: 962, 1973. Pujol-Amat, P., O. Gamissans, J. Calaf, E. Benito, F. R. Perez-Lopez, M. L'Hermite, and C. Robyn, In Pasteels, J. L., and C. Robyn (eds.), Human Prolactin, Int. Congr. Ser. No. 308, Excerpta Medica, Amsterdam, 1973, p. 316. Schwers, J., Les Oestrogenes au Cours de la Seconde Moitie de la Grossesse, Arscia S. A., Brussels, 1964. Loriaux, D. L., H. J. Ruder, D. R. Knab, and M. B. LipsettJ Clin Endocrinol Metab 35: 887, 1972. Buckman, M. T., and G. T. Peake, J Clin Endocrinol Metab 37: 997, 1973. L'Hermite, M., P. Delvoye, J. Nokin, M. Vekemans, and C. Robyn, In Boyns, A. R., and K. Griffiths (eds.), Prolactin and Carcinogenesis, Alpha Omega Alpha Publishing Co., Cardiff, U.K., 1972, p. 64.

889

11. Frantz, A. G., D. L. Kleinberg, and G. L. Noel, Recent Progr Horm Res 28: 527, 1972. 12. Robyn, C , M. L'Hermite, P. Petrusz, and E. Diczfalusy, Ada Endocrinol (Kbh) 67: 417, 1971. 13. Odell, W. D., and M. Hescox, In Margoulies, M., and F. C. Greenwood (eds.), Protein and Polypeptide Hormones, Int. Congr. Ser. No. 241, Excerpta Medica, Amsterdam, p. 241, 1972. 14. Badawi, M., S. Bila, M. L'Hermite, F. R. PerezLopez, and C. Robyn, In Radioimmunoassay and Related Procedures in Medicine, International Atomic Energy Agency, Vienna, 1974, p. 411. 15. Yen, S. S. C , Y. Ehara, and T. M. Siler, J Clin Invest 53: 652, 1974. 16. Robyn, C , and M. Vekemans, In Van Keep, P. A., and C. Lauritzen (eds.), Estrogens in the Postmenopause, S. Karger, Basel, 1975, (In press). 17. Yen, S. S. C , C. C. Tsai, F. Naftolin, G. Vandenberg, and L. Ajabor, J Clin Endocrinol Metab 34: 671, 1972. 18. Wide, L., S. J. Nillius, C. Gemzell, and P. Roos, Ada Endocrinol (Kbh) Suppl. 174, 1973. 19. Delvoye, P., H.-D. Taubert, O. Jurgensen, M. L'Hermite, J. Delogne, and C. Robyn, CR Acad Sci [D] (Paris) 279: 1463, 1974.

Elevation of Serum Testosterone in Ovarian Hyperstimulation Syndrome1 Z. SCHUMERT, I. SPITZ, Y. DIAMANT, W. Z. POLISHUK, AND D. RABINOWITZ Departments of Chemical Endocrinology and of Obstetrics and Gynecology, Hadassah University Hospital, Jerusalem, Israel ABSTRACT. Serum testosterone levels were monitored in female subjects who received therapy with human gonadotropins of urinary origin (menotropins) and human chorionic gonadotropin (hCG). Serum testosterone levels were not elevated in those subjects who did not experience side effects with therapy (Group A); among the other 7 subjects (Group B) with either moderate or severe ovarian

^CONCENTRATIONS of testosterone in V>< peripheral plasma or serum among normal women are low (usually less than 1 ng/ml) and show only modest changes through the menstrual cycle. Goebelsmann et al. (1) measured serum testosterone in 40 women and reported a mean Received October 10, 1974. 1 Supported by Mifal Hapayis, The Population Council and Israel Center for Psychobiology. During the course of this work, D. R. was an established investigator, Israeli Ministry of Health.

hyperstimulation, serum testosterone levels rose distinctly (range 1.4—9.0 ng/ml). Total menotropin

dosage and serum estradiol-17/3 levels were higher in Group B than in Group A. Ovarian hyperstimulation and elevation of serum testosterone were not restricted to patients with the syndrome of polycystic ovaries. (/ Clin Endocrinol Metab 40: 889, 1975)

value of 0.35 ng/ml, with the highest average testosterone concentration, 0.42 ng/ml, on the day of the hLH peak. The same laboratory has also reported a rise in serum androstenedione concentrations in women during the late follicular phase and around the time of ovulation (2). Others have made similar observations (3,4). Mikhail examined the level of several steroids directly in the venous effluent from the human ovary, and reported that the ovary secreted significant amounts of androstenedione, but direct secretion of testosterone was exceedingly

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small (5). By contrast, in 1 subject with polycystic ovarian disease who had been treated with clomiphene citrate, ovarian vein testosterone levels were 20 and 65 ng/ml and the peripheral venous concentration was 7.5 ng/ml. Dupon et al. reported an increase in androstenedione and testosterone levels in 3 of 5 women with oligomenorrhea who had been treated with clomiphene citrate (6). Both Mikhail and Dupon et al. suggested that the high concentrations of androgen may reflect ovarian hyperstimulation in response to the clomiphene-induced gonadotropin secretion. In this communication we report a significant rise in serum testosterone among women treated with human gonadotropins of urinary origin (menotropins) and hCG. Elevation in serum testosterone concentration was correlated with clinical and biochemical evidence of ovarian hyperstimulation.

having the polycystic ovarian syndrome, and subject 2 had previously undergone ovarian wedge resection. Subject 9 is presented in detail. The other patients exhibited anovulatory cycles, and all had had unsuccessful treatment with clomiphene citrate.

Results

Results are shown in Table 1 and in Fig. 1. Subjects 1 to 5 received menotropins in dosages which ranged from 600-1275 IU. The highest estradiol-17/3 was 405 pg/ml, and all serum testosterone levels were less than 1 ng/ml. Subjects 6 to 11 exhibited either moderate or severe hyperstimulation syndrome (5). The menotropin dosage was higher than among Group A subjects (1500-2900 IU) as were serum estradiol17/3 levels (775-1240 pg/ml). Serum testosterone levels were uniformly elevated although the increase varied widely. Subject 1 was given a subsequent course of menotropins to a total dosage of 1500 IU. On this occasion she deMaterials and Methods veloped hyperstimulation syndrome, and serum Frequent hFSH, hLH, estradiol-17/3, progesterone testosterone levels rose to 2.5 ng/ml. Figure 1 displays the march of events in and testosterone values were determined throughout the menstrual cycle in nine of our patients treated, subject 9. She had had a normal history until with menotropins (Pergonal 500, Ikapharm, Israel) 5 yr prior to study. Menarche occurred at age 11, and hCG (Pregnyl, Organon, Holland). Serum testos- and at age 27 she had had a normal pregnancy. terone levels were also determined in two additional Two years later she was involved in a traffic patients, admitted to our hospital with overt signs of accident with multiple injuries, after which she ovarian overstimulation syndrome (7). We have divided had no further spontaneous menstrual periods. the patients into two groups (Table 1): Group A, in Serum hFSH, hLH and estradiol-17/3 levels whom no side effects were noted, and Group B, who were at the lower limit of detection of our exhibited evidence of ovarian hyperstimulation; that assay. Laparoscopy revealed normal but inactive is, an increase in ovarian size to twice normal or ovaries without signs of ovulation. Other tests greater, and lower abdominal pain with or without of endocrine function were within normal limits. ascites. Subjects 2 and 10 had been diagnosed as TABLE 1. Summary of patients' data* Therapy (total units) Subject no.

Ka) 2 3 4 5

Kb)

6 7 8 9 10 11

hMG(IU)

hCG (IU)

600 675 1,030 1,125 1,275 1,500 1,500 1,895 2,025 2,100 2,175 2,950

10,000 10,000 10,000 10,000 15,000 25,000 10,000 10,000 10,000 10,000 5,000 5,000

Maximum serum levels E2, pg/ml 125 355 200 405 130 1,000 775 1,240 1,100 830 1,000

T (ng/ml)

Conception

0.75 1.0 0.56 0.95 0.85 2.5 3.6 1.4 1.4 2.5 9.0 3.7

No No Yes Yes No Yes Yes Yes No Yes Yes (twins) Yes (quads)

* Patients 1 to 5 (Group A) exhibited no side effects with therapy. Patient 1 was given a further course of therapy (lb). Patients l(b) and 6 to 11 comprise Group B, in whom signs of ovarian hyperstimulation developed.

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COMMENTS

hMG M.A.

B hCG

FSH

30 20 10 0

\ •

i

;

LH m.l.U./ml

30

J

20 10 FlG. 1. Hormonal profile and details of therapy in subject 9. Dosage of hCG was 10,000 IU. Each closed square of hMG (menotropins, Pergonal) represents 75IUof FSH.

o Estradiol-120° 17OH-P 600 pg/ml Progesterone ng/ml

/

V

30 20

Testosterone ng/ml

12

16 20 August

1974 Details of therapy are shown in Fig. 1. Eight days after hCG administration, the patient developed severe lower abdominal pain and large bilateral ovarian cysts were noted. The serum estradiol level was 1100 pg/ml and the serum testosterone was 2.5 ng/ml.

Discussion We have presented data on a group of infertile female patients who were treated with exogenous gonadotropins. We confirm that there is a relationship between the dosage of menotropins administered and the appearance of ovarian hyperstimulation syndrome. Of considerable interest is the elevation in serum testosterone observed in the latter group (Table 1). This is concordant with the experience of

24

28

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Mikhail (5) and of Dupon et at. (6). Mikhail's one subject had enlargement of the ovaries bilaterally, and multiple corpora lutea were found in each ovary. Secretion of progesterone, 17a-hydroxyprogesterone, androstenedione and testosterone were markedly elevated. Of the 3 subjects reported by Dupon et at. with levels of androstenedione and testosterone 2 SD above normal, 2 had progesterone levels exceeding 30 ng/ml, values which suggest ovarian hyperstimulation. It is likely that under supra-optimal influence of exogenous gonadotropins (hMG and hCG), many enzyme systems are activated, and the synthesis of a host of steroids is enhanced (8,9). While hCG has little effect on serum testosterone levels in normal women (1), it can produce appreciable increases in women with "idiopathic hirsutism" (4,10). Hyperstimulation

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JCE & M • 1975 Vol 40 • No 5

4. Lloyd, C. W., J. Lobotsky, E. J. Segre, T. Kobayashi, M. L. Taymor, and R. E. Batt, J Clin Endocrinol Metab 26: 314, 1966. 5. Mikhail, G., Gynec Invest 1: 5, 1970. 6. Dupon, C , R. L. Rosenfield, and R. E. Cleary, Am] Obstet Gynecol 115: 478, 1973. 7. Rabau, E., A. David, D. M. Serr, S. Masiach, and B. Lunenfield, Am J Obstet Gynecol 98: 92, References 1967. 1. Goebelsmann, U., J. J. Arce, I. H. Thorneycroft, 8. Yoshimi, T., C. A. Strott, J. R. Marshall, and M. B. and D. R. Mishell, Jr., Am J Obstet Gynecol LipsettJ Clin Endocrinol Metab 29: 225, 1969. 119: 445, 1974. 9. Mishell, D. R., Jr., I. H. Thorneycroft, Y. Nagata, 2. Ribeiro, W. O., D. R. Mishell, Jr., and I. H. and R. M. Nakamura, In Rosemberg, E. E. (ed.), Thorneycroft, Am J Obstet Gynecol 119: 1026, Gonadotropin Therapy in Female Infertility, 1974. Excerpta Medica, 1973, p. 235. 10. Rosenfield, R. L., E. N. Ehrlich, and R. E. Cleary, 3. Judd, H. L., and S. S. C. Yen, J Clin Endocrinol J Clin Endocrinol Metab 34: 92, 1972. Metab 36: 475, 1973.

syndrome with elevation of serum testosterone levels is, however, not confined to such subjects. Thus subject 9 who displayed low hFSH and hLH levels and inactive ovaries also developed the syndrome after menotropin therapy.

Effect of Synthetic Luteinizing Hormone Releasing Hormone (LH-RH) on the Release of Gonadotropins in Cushing's Disease GIUSEPPE BOCCUZZI, ALBERTO ANGELI, DANIELA BISBOCCI, DOMENICO FONZO, GIAN PIERO GAIDANO, AND FRANCO CERESA Istituto di Patologia Medica and Istituto oh Semeiotica Medica Universita degli Studi, Torino, Italy ABSTRACT. The effect of intravenous synthetic luteinizing hormone releasing hormone (LH-RH) on plasma radioimmunoassayable levels of gonadotropins was investigated in 6 women suffering from Cushing's disease with bilateral adrenal hyperplasia. In five of six cases no significant variation of plasma LH levels was found following stimulation; in one case the response to LH-RH was present

although slightly reduced below the normal range. By contrast in all cases the plasma FSH response was similar to that recorded in normal subjects. The explanation of impaired LH response is not clear but the possibility that endogenous hypercortisolism affects the pituitary responsiveness to LH-RH has to be considered. (/ Clin Endocrinol Metab 40: 892, 1975)

A MENORRHEA is frequently present in _/~JL women suffering from Cushing's disease. Very little is known of the hypothalamic control of gonadotropin secretion in this disease although central nervous disturbances have been indicated not only in the control of ACTH but also of GH secretion (1). Studies on plasma radioimmunoassayable gonadotropin levels led to contradictory results: normal, elevated or reduced plasma FSH and LH values have been reported (2,3,4). The response of plasma gonadotropin to synthetic luteinizing hormone releasing hormone (LH-RH), was shown to be reduced (5) or normal (6) in Cushing's disease. The purpose of the present study was to investigate the effect of intravenous synthetic

LH-RH on plasma radioimmunoassayable levels of gonadotropin in patients with Cushing's disease.

Received July 29, 1974.

Materials and Methods Six women aged between 28 and 68 yr, suffering from Cushing's disease with bilateral adrenal hyperplasia were examined. Diagnosis was achieved on the basis of common laboratory tests, including adrenal scintiscan with iodinated cholesterol and retroperitoneal insufflation. One patient was postmenopausal; in the others amenorrhea had lasted from 6 to 30 months. One hundred micrograms of synthetic LH-RH was given by rapid intravenous injection over a period of 10 s between 8:00 and 9:00 AM to the fasting subjects. Blood samples were taken from an indwelling iv catheter 10 min before the administration of LH-RH and then at zero time and at 10, 20, 30, 40, 60, 90, 120, 150 and 180 min following the

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Elevtion of serum testosterone in ovarian hyperstimulation syndrome.

Serum testosterone levels were monitored in female subjects who received therapy with human gonadotropins of urinary origin (menotropins) and human ch...
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