Fetal protection against masculinization with hyperreactio luteinalis and virilization.

Fetal Protection Against Masculinization with Hyperreactio Luteinalis and Virilization P. A. HENSLEIGH, R. P. CARTER, AND H. E. GROTJAN, JR. Department of Gynecology and Obstetrics and Ralph L. Smith Human Development Center, University of Kansas School of Medicine, Kansas City, Kansas 66103

Research

normal level, the material ovarian vein level was 51,800 ng/dl, while the cord blood level was only 465 ng/dl. At the same time there was an increase in fetal cord blood estradiol to 33 ng/ml, a 7-fold increase compared to normal cord levels. A protective mechanism for the fetus may exist when maternal androgens are markedly elevated due to a maternal endocrinopathy concurrent with pregnancy. Our data are compatible with the concept that placental aromatization of androgens may function as a metabolic barrier, thus offering protection to the fetus from excessive maternal androgens. Another facet of the protective mechanism may be increased fetal exposure to potent estrogens, which may buffer the influence of androgens reaching the fetus. (J Clin Endocrinol Metab 40: 816, 1975

ABSTRACT. In a unique patient with secondary amenorrhea and hirsutism prior to pregnancy, lutein cysts with hyperreactio luteinalis enlarged the ovaries to a diameter of 25 cm during pregnancy. The purpose of the study was to explore the possibility that placental aromatization of androgens may be a metabolic barrier that offers protection against masculinization of a female fetus. Maternal serum, umbilical cord serum and lutein cyst fluid were analyzed for testosterone, progesterone and estradiol content. The cardinal clinical findings were marked maternal virilization but no fetal masculinization. At the time of delivery, massive ovarian production of testosterone and a large maternal-fetal testosterone gradient were found. The maternal arm vein testosterone level, 15,000 ng/dl, was about 100 times

O

VARIAN lutein cysts occur commonly in pregnant patients with trophoblastic disease, occasionally with multiple gestations or erythroblastosis and rarely in normal pregnancy. The microscopic findings in such ovaries include multiple cystic follicles of variable size with striking hypertrophy of the theca internal cells, often in alveolar arrangements permeating the stroma in irregular masses. Regardless of associated conditions in the pregnancy, grossly and histologically these cystic ovaries are identical. Although virilization accompanying hyperractio luteinalis has not previously been reported as such, we will discuss three previously reported cases that appear to represent the same disorder. Case Report A 25-yr-old Black woman, now gravida 1, para 1, with one living child, had menarche at age 14 Received September 5, 1974. Reprint requests should be addressed to Paul A. Hensleigh, M.D., Ph.D., Department of Gynecology and Obstetrics, University of Kansas Medical* Center, 39th and Rainbow, Kansas City, Kansas 66103.

and first presented at this hospital at age 17 for evaluation of amenorrhea and increased hair growth of one year duration. She had normal female stature and breast development. Despite the patient's concern about hirsutism, the examiner was not impressed with any excessive or abnormally distributed hair. Laboratory examinations included a PBI (5.5 /u,g/dl), maturation index (0/76/24), 17-ketosteroids (2.9 to 7.9 mg/24 h) and sella turcica x-rays. All results were within normal limits. She was treated for hypothalamic amenorrhea over the subsequent 2 yr with intermittent medroxy-progesterone for induction of withdrawal bleeding. During this time her hirsutism was thought to be somewhat progressive. At age 20 she began having regular menses without hormone therapy and she was placed on sequential oral contraceptives for birth control.* After 6 months she stopped taking this medication, and two subsequent bleeding episodes and then became amenorrheic again. She received medroxy-progesterone to stimulate withdrawal flow episodically during the next 2 yr and was subsequently seen at age 24 for infertility and hair loss (occipital alopecia), amenorrhea of 3 * 80 fig mestranol days 5-19; 2 mg chlormodinone acetate 80 fig mestranol days 20-24 each cycle. C-Quens (Lilly).

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FETAL PROTECTION AGAINST MASCULINIZATION months following progesterone withdrawal, postcoital spotting and a swelling of the labia. She was admitted to the hospital for a diagnostic D&C, laparoscopy and marsupialization of a Bartholin's cyst. However, under anesthesia, enlargement of the uterus suggestive of an 8 week pregnancy was discovered and the planned diagnostic procedures were abandoned. An immunologic test for pregnancy was positive. Her pregnancy progressed uneventfully until 28 weeks gestation when the uterine fundus was noted to be abnormally large. A moderate positive tape test for urine glucose was also noted. Blood glucose was 86 mg/dl 2 h postprandial. At this time a single fetus was demonstrated on x-ray. A dermatologist reported that she had moderately severe acne of the face, back and chest and mild hirsutism of the face and neck, but by history these problems had not been progressive in the previous year. No other signs of virilization were found though she continued to complain of increasing hirsutism. The patient was admitted to the delivery area

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at term by estimated dates with ruptured membranes and had a spontaneous onset of labor. She had moderately severe acne, generalized hirsutism of the face, chest, abdomen and legs. Clitoral hypertrophy was not noted on admission but was later described. Labor was complicated by failure of the vertex to descend and variable decelerations of the fetal heart rate. The patient was delivered by cesarean section. On opening the abdomen the ovaries were found to be massively enlarged. A female with normal external genitals was delivered and it was found that the umbilical cord was wrapped around the neck in five loops. The placenta was examined grossly and microscopically and the only abnormality noted was interstitial hemorrhage of the unbilical cord. The patient's ovaries were cystic and enlarged to approximately 25 x 12 x 5 cm each (Fig. 1). A portion of the left ovary, removed for histologic examination, was interpreted as hyperreactio luteinalis (Fig. 2). Ovarian cyst fluid, ovarian vein, peripheral and umbilical

FIG. 1. Cystic ovaries observed after cesarean section.


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HENSLEIGH, CARTER AND GROTJAN

FIG. 2. Ovarian biopsy intrapartum. (x43) cord blood samples were obtained for steroid analysis. Urine collections were begun immediately postpartum for steroid determinations. Peripheral venous samples were obtained 3V2, 23 and 36 weeks after delivery. Samples 23 and 36 weeks post-delivery were taken after suppression of the hypothalamic-pituitary axis with contraceptive steroids.**

sample were assayed in duplicate and the value reported for a particular steroid is the mean concentration of volumes from the portion of the dilution curve which was parallel to the standard curve. Interassay coefficient of variation between duplicates for the testosterone RIA was 11.5%, progesterone RIA was 9.7% and estradiol RIA was 12.7%. Since serum and ovarian cyst fluid testosterone concentrations were extremely elevated at delivery and 3Y2 weeks post-delivery, they were confirmed by analysis in another laboratory using the method of Furuyama et al. (3) and anti-testosterone-3-oxime-bovine serum albumin (No. T-432, Inter/Science Institute, Los Angeles, Calif.). Values obtained in their testosterone RIA with purification were in excellent agreement with those obtained in the RIA not employing the purification step except as noted in the Table 1 footnote.

Results

Steroid determinations and reported normal values are shown in Table 1. The most striking results are the testosterone concentrations at the time of delivery. The Materials and Methods peripheral level of testosterone is more The steroid concentrations in serum and ovar- than 100-fold greater than the reported ian cyst fluid were measured by specific radionormal mean for term pregnancy. The immunoassays (RIA). Samples were diluted to concentration in ovarian venous and cyst 1.0 ml with distilled water, extracted one time fluid, which is even higher, indicates that with 3.0 ml freshly opened diethyl ether and the testosterone was being produced in the steroids measured in the residue. Procedural ovaries. In contrast to these extremely high losses were determined by representative relevels in the patient, her fetus had much covery samples. Each tube of the standard curve lower levels as indicated by analysis of the received a 3.0 ml extract of 1.0 ml distilled water to eliminate "blanks" resulting from ex- cord blood. The discrepancy between testraction. Anti-testosterone-6-mercaptosuccinyl- tosterone concentrations as determined by bovine serum albumin and anti- progesterone- the two methods (464 vs 252 ng/dl) would 6-mercaptosuccinyl-bovine serum albumin were appear to be significant and may indicate grown in rabbits and are specific for their the presence of another steroid that cross respective steroids except that the anti-tes- reacts with testosterone which, however, tosterone cross-reacts approximately 60% with was removed by the purification step in the 5a-dihydrotestosterone (1). Anti-17-B-essecond method. tradiol-6- (0-carboxymethyl) oxime-bovine serum Maternal peripheral progesterone and albumin was grown in rabbits and is highly specific for estradiol (2). All RIA's were per- estradiol are both in the lower portion of formed in phosphate buffered saline (0.1M, the normal range for term pregnancy. Again pH = 7.0) containing 0.1 g/dl gelatin and 0.1 there obviously was significant progesg/dl sodium azide. Several volumes of each terone and estrogen production by the ovaries. Since the ovarian venous sample ** 2.5 mg norethynodrel and 100 fig mestranol. was obtained following removal of the fetus and placenta, the increased levels in Enovid-E (Searle).


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FETAL P R O T E C T I O N AGAINST MASCULINIZATION TABLE 1. Steroid concentrations in a patient with hyperreactio luteinalis and virilization

Hormone Testosterone Testosterone Testosterone Testosterone Testosterone Testosterone Testosterone Progesterone Progesterone Progesterone Progesterone Progesterone Progesterone Progesterone Estradiol Estradiol Estradiol Estradiol Estradiol Estradiol Estradiol a b

Weeks after delivery 0

a

3% 23 36 0

3y2 23 36 0

23 36

Sample source

Result

Normal mean

Peripheral venous Ovarian venous Ovarian cyst fluid Cord mixed serum Peripheral venous Peripheral venous Peripheral venous

15,000 ng/dl 51,800 53,700 465b 341 66 72

114-150(4,5)


90 ng/ml 417 1,040 485 1.8 0.8 0.9


11 ng/ml 43 51 33 0.08 0.01 0.03

46-48 (4,5) 69(6) 175 (7) 590 (8) 0.49 (6) 16(7) 4.8 (9) 0.085 (6)

Intrapartum sample during cesarean section. This value was not confirmed by the Furuyama method which indicated 252 ng/dl.

ovarian compared to peripheral veins do not represent steroids shunted through uterine-ovarian anastamoses. The cord blood samples show an elevation of estradiol concentration to about 7 times normal and a progesterone concentration only slightly below the normal mean. In contrast to the usual gradient, estradiol was higher in the cord than in the peripheral maternal circulation. Following delivery the 3%, 23 and 36 week samples show that all the assayed steroids returned to levels comparable to those reported for women on oral contraceptives. In addition to the serum steroid determinations in Table 1, urinary excretion of 17-ketosteroids (17-ks) were found to be 82 mg/24 h and 17-ketogenic steroids (17-kgs) were 71 mg/24 hours in a specimen collected during the first 24 h postpartum. The total volume of the sample was 2000 ml and it contained 1.8 g of creatinine. Interpretation of these data is difficult since

we assume that the patient's endocrinopathy was rapidly resolving during the collection period. The stress of hospitalization, labor and laparotomy under general anesthesia undoubtably contribute to the elevation of 17-kgs. Serum hCG at delivery was found to be 70,000 mlU/ml by the Trophoblastic Disease Center Laboratory, University of Texas, M.D. Anderson Hospital using a nonspecific hCG-LH radioimmunoassay. Since this value was higher than normal term levels reported in the literature, 12 normal term patients from our obstetrical population had serum samples drawn for hCG analysis by the same laboratory. The mean level of hCG in these samples was 34,500 mlU/ml ± 23,800 (SD). Thus, our virilized patient had an hCG concentration in the upper normal range. The serum FSH level was 26 ng/ml determined by radioimmunoassay in the Clinical Metabolic Research Laboratory, University of Kansas Medical Center. This


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value is at the lower limits of sensitivity of their assay technique and is not abnormal for term pregnancy. Discussion Androgen Metabolism in pregnancies with hyperreactio luteinalis In reviewing the literature we found three cases very similar to the one reported here. Alexander and Beresford (11) in 1953 reported a patient with a similar clinical course who excreted 100 mg/24 h of 17-ks 1 month after delivery. Jewelewicz et al. (12) reported a "luteoma" causing maternal virilization. The gross description, however, is typical for multiple lutein cysts rather than luteoma of pregnancy. Through the courtesy of the authors we examined the microscopic slides of that tumor which appears to represent hyperreactio luteinalis, although luteoma could only be completely ruled out with a reticulum stain. The steroid levels also approximate those in our case: peripheral venous testosterone = 11,500 ng/dl, 17-ks = 89 mg/24 h, and 17-kgs = 51 mg/24 h. Judd et al (13) reported a twin pregnancy with maternal virilization and theca lutein cysts, but steroid studies were not done until 8 weeks postpartum. At that time the serum testosterone was only slightly elevated (91.2-139.4 ng/dl): the testosterone level was decreased by dexamethasone and increased by hCG administration. Thus we believe this to be the fourth reported case of lutein cystic ovaries (hyperreactio luteinalis) and maternal virilization not associated with trophoblastic disease. Patients with hydatidiform mole or choriocarcinoma often have multiple lutein cystic ovaries and hyperreactio luteinalis undistinguishable from those seen in nonmolar pregnancies. Though moles are not commonly associated with clinical virilization, Samaan et al. (14) have found increased serum testosterone levels in patients with hydatidiform mole and choriocarcinoma. The greatest increase of

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testosterone was found in those patients who also had enlarged (cystic) ovaries. Their evidence substantiates that the ovaries, and not the trophoblastic tissues, were the site of testosterone production. The magnitude of testosterone synthesis in their patients is considerably less than in our patient. Peripheral serum levels of testosterone as high as 790 ng/dl and ovarian cyst fluid levels of 3765 ng/dl were found by them in mole patients with large ovaries. The clinical course of our patient was comparable to the non-molar cases discussed above with apparently the same disorder. These similarities and the applicable steroid assays are outlined in Table 2. Three of these 4 patients had oligomenorrhea and/or some virilization preceding the pregnancy. The levels of serum testosterone and urinary 17-ks are of the same order, though the time lapse from delivery was variable. None of the 3 female fetuses reviewed in Table 2 were masculinized although these effects were specifically sought in each infant. In our study and that of Jewelewicz et al. (12) the virilized mothers had serum tesotsterone levels many-fold greater than normal, yet the female fetus was not masculinized in either case. One possibility is that the lack of fetal masculinization in both cases was due to late onset of fetal androgen exposure during the pregnancy. The clinical onset of maternal virilization in the cases in Table 2 ranged from 5 to 7 months of gestation. Thus, it is clear that the onset was early enough in gestation to result in marked maternal virilization by the time of delivery. Because of this difference, maternal virilization with essentially no fetal androgen effects, other protective mechanisms for the fetus should be considered. One explanation for the observed lack of fetal masculinization could be that the placenta serves as a partial barrier to excessive maternal testosterone levels. Although cord serum testosterone was not measured


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TABLE 2. Reported cases of virilization in pregnancy with presumed hyperreactio luteinalis Author

Anovulation or oligomenorrhea

Course of pregnancy

Steroid studies

Alexander and Beresford (11)

Always irregular 28-56-day cycles

Deepening voice—4 months Hirsutism—6 months Female fetus—healthy

17-ks = 100 mg/24 h (1 mo. pp)

Jewelewicz and associates (12)

Regular menses Every 28-30 days

Hirsutism—7 months Female fetus with no virilization

17-ks = 88.8 mg/24 h (1 d. pp) 17-kgs = 50.9 mg/24 h (1 d. pp) T = 11,500 ng/dl (a)

Judd and associates (13)

Always irregular menses 3-4 month intervals Some acne

Hirsutism—5 months Twin male fetuses

17-ks = 11 mg/24 h (2 mo. pp) T = 91-140 ng/dl (2 mo. pp)

Present case

Oligomenorrhea and amenorrhea

Increasing hirsutism and acne—7 months Female fetus with no virilization

T = 15,000 ng/dl (del. day) T = 341 ng/dl (24 days pp) 17-ks = 82 mg/24 h (1 d. pp) 17-kgs = 71 mg/24 h (1 d. pp)

(a) Competitive protein binding method: 1,460 ng/dl by double isotope derivative method.

in the previous reports, in our case the cord level of 465 ng/dl was 3% of the measured maternal peripheral serum concentration of 15,000 ng/dl. This data indicates a striking difference of exposure to testosterone for the mother and fetus, and is compatible with at least a partial placental barrier mechanism. At the same time the absolute fetal testosterone level is about ten times the reported normal fetal level (4,5). Since an adult with similar serum testosterone levels would be expected to develop virilization, the partial placental barrier does not totally explain the lack of fetal masculinization. One could still hypthesize that the fetal exposure was too brief for profound effects. Moreover, the sensitivity of the fetus to testosterone may be less than in a normal adult. Blunting of testosterone sensitivity in the fetus could be due to excessive estradiol exposure during the same period. While the serum level of testosterone in the mixed cord blood was 465 ng/ml, estradiol was 33 ng/ml (3300 ng/dl). This level of estradiol is about seven times the reported

normal mean of 4.8 ng/ml (9). The elevation of fetal estradiol took place in the absence of increased maternal estradiol concentration and, as a result, there is a reversal of the usual maternal fetal gradient for estradiol. Our data are compatible with the suggestion by Gandy (15) that fetal androgen exposure may be minimized by efficient placental aromatization of androgens entering the placenta from the mother. In a pregnancy with excessive maternal testosterone the determinants of morphogenesis of fetal genitals may include: 1) the duration of fetal testosterone exposure, 2) the efficiency of the partial placental barrier, and 3) the blunting effect of increased fetal estrogens. The latter two phenomenon may have been operative in our case. One particularly interesting finding among the data in Table 1 is that there is an obvious increase in progesterone in ovarian vein and cyst fluid. Thus it is evident that there was a general increase in steroidogenesis which was not specifically productive of testosterone. The clinical


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picture of maternal virilization must therefore be interpreted as a relatively greater production of androgen in comparison to other steroids. The 3y2 week postpartum data illustrate that the ovaries were returning toward normal even though no specific therapy was instituted and only a small biopsy of the ovary was taken at the time of the cesarean section. Because the tumors were persistent and the virilization persisted at this time, the patient was placed on an oral contraceptive for pituitary suppression. Subsequent steroid levels were comparable to reported normals for patients taking oral contraceptives. While both luteoma and hyperreactio luteinalis are hyperplastic lesions (not neoplastic) and seldom require surgical excision per se, extensive evaluation is necessary to establish such a diagnosis since one can anticipate a malignancy rate of 50% when virilization accompanies ovarian tumor in pregnancy (16). Thus, it is obviously necessary not only to visualize the ovaries in such a case but also to obtain tissue for histologic sections. Gonadotropins in pregnancies with hyperreactio luteinalis The theca lutein cystic ovaries commonly found in association with hydatiform mole and choriocarcinoma have logically been explained by excessive hCG stimulation. Caspi et al. (17) have reviewed 29 cases of hyperreactio luteinalis in the literature which were not related to trophoblastic disease; none of these were virilized. Increased hCG could be assumed in 13 of these cases in which there were multiple gestations (6) or severe Rh sensitization (7). The remaining 16 patients had apparently normal pregnancies. Since the histologic picture of hyperreactio luteinalis is identical in association with trophoblastic disease, multiple pregnancies, Rh sensitization and normal pregnancy, one might anticipate a common etiology. However logical it might seem to incriminate in-

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creased hCG, very little data is available to support this mechanism in the apparently normal pregnancies; of the 5 patients evaluated for hCG levels, only 2 were abnormally elevated. The fetus of 1 of these was a monster with an intracranial teratoma. Among the 3 previously reported cases of hyperreactio luteinalis with virilization (in Table 2) only 1 patient was evaluated for hCG and in this case the urinary excretion of 84,840 ng/24 h was interpreted as normal (12). As mentioned above, our patient had hCG levels near the upper normal range for term pregnancy. Serum hCG was assayed in our laboratory at 3Vz and 23 weeks postpartum and decreased normally to 10 mlU/ml and 2 mlU/ml respectively. One year following delivery the patient's ovaries were still enlarged by sonography and some virilization persisted. To further evaluate a possible role of hCG in our patient's disease process and to provide her with a prognosis of subsequent pregnancy, she was re-admitted to the hospital. At this time she was still taking oral contraceptives.** Baseline studies revealed 17-ks of 5.8 mg/24 h. Baseline serum testosterone levels were 51-65 ng/dl. Subsequently the patient received an intravenous infusion of 5,000 IU of hCG over 4 h for a stimulation test according to the protocol of Vivanco (18) in which no response (in serum testosterone) is expected in normal females. Serum samples throughout the subsequent 48 hours showed no values above baseline and the 24-h excretion of 17-ks did not increase. The conclusion from this study was that if the patient's ovaries were stimulated to produce testosterone by hCG during the previous pregnancy, this sensitivity no longer existed. Obviously the significant dosage difference could account for the observation. Following completion of the hCG stimulation test, laparoscopy was performed. The ** Enovid-E (Searle).


FETAL PROTECTION AGAINST MASCULINIZATION

ovaries were 5 x 3 x 1 cm in size with multiple white fibrous tissue. A biopsy, obtained from the right ovary, showed only extensive focal fibrosis. These findings confirm that the patient previously had an ovarian hyperplasia which essentially reached complete regression within a year. Acknowledgments This work was supported in part by the Associates in Gynecology and Obstetrics Chartered, University of Kansas and NIH General Research Support Grant 5S01-PR-5373. Assays for hCG were done by the Trophoblastic Disease Lab, M.D. Anderson Hospital and confirmatory testosterone assays by the Metabolic Research Lab, University of Kansas Medical Center. We wish to acknowledge the secretarial assistance of Mss. Jan Prather and Syd Olson, the technical assistance of Ms. Muriel Wagner and Walter Leslie, the help of Dr. T. Fainstat in manuscript preparation, the pathology consulting service of Dr. F. Mantz and the courtesy of Dr. R. Vande Wiele in sending details of a previously reported case. The generous gift of 17)8estradiol antibody by Doctors Exley, Johnson and Dean is acknowledged.

References 1. Pang, C. N., and D. C. Johnson, Steroids 23: 203, 1974. 2. Exley, D., M. W. Johnson, and P. D. G. Dean, Steroids 18: 605, 1971. 3. Furuyama, S., D. M. Mayes, and C. A. Nugent, Steroids 16: 415, 1970.

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4. Rivarola, M. A., M. G. Forest, and C. J. Migeon,/ Clin Endocrinol Metab 28: 34, 1968. 5. Mizuno, M., J. Lobotsky, C. W. Lloyd, T. Kobayashi, and Y. Murasawa, J Clin Endocrinol Metab 28: 1133, 1968. 6. Briggs, M., and M. Briggs, / Obstet Gynaecol Br Commonw 79: 946, 1972. 7. Tulchinsky, D., C. J. Hobel, E. Yeager, and J. R. Marshall, AmJ Obstet Gynecol 112: 1095, 1972. 8. Laatikainen, T., J. Peltonen, and P. Nylander, Steroids 21: 347, 1973. 9. Shutt, D. A., I. D. Smith, and R. P. Shearman, / Endocrinol 60: 333, 1974. 10. Huis in t Veld, L.G., Gynec Obstet 53: 42, 1954. 11. Alexander, W. S., and O. D. Beresford, J Obstet Gynaecol Br Commonw 60: 252, 1953. 12. Jewelewicz, R., R. P. Perkins, I. Dyrenfurth, and R. L. Vande Wiele, Am J Obstet Gynecol 109: 24, 1971. 13. Judd, H. L., K. Benirschke, G. Devane, S. R. Reuter, and S. S. C. Yen, N Engl J Med 288: 118, 1973. 14. Samaan, N. A., J. P. Smith, F. N. Ruteledge, and J. M. Barcellona, / Clin Endocrinol Metab 34: 558, 1972. 15. Gandy, H. M., In Fuchs, F., and A. Klopper (eds.), Endocrinology of Pregnancy, Harper and Row Publishers, New York, 1971, p. 101. 16. Verhoeven, A. T. M., J. L. Mastboom, H. A. I. M. Van Leusden, and W. H. M. Van der Velden, Obstet Gynecol Survey 28: 597, 1974. 17. Caspi, E., P. Schreyer, and J. Bukovsky, Obstet Gynecol 42: 388, 1973. 18. Vivanco, F., P. Gonzalez-Gancedo, and F. Ramos, Ada Endocrinol 73: 790, 1973.


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