The use of human menopausal and chorionic gonadotropins for induction of ovulation

GYNECOLOGY

The use of human menopausal and chorionic gonadotropins for induction of ovulation Sixteen years' experience at the Sloane Hospital for Women ivi () S H E S C H VV A. R"[ Z, ivi . D . RAPHAEL JF:WELF:WICZ. M.D. 17\!GE DYRE7\!fTRTH, PH.D.

P.\MELA TROPPER. M.D. RAYMOND L. VANDE WIELE, M.D.

N1•w York, New York Gonadotropin therapy for anovulation is highly successful: 58.6% of treated patients conceive. Better results are achieved in patients with galactorrhea-amenorrhea (n.1%) and hypogonadotropic hypogonadism (63.3%) than in patients with normal gonadotropin levels (45.4%). The spontaneous abortion rate (27.5%) is somewhat higher than that in spontaneous pregnancies. The multiple pregnancy rate is 31% and was slightly lower in cycles with preovulatory estrogen levels in the physiologic range. In patients treated with human menopausal and chorionic gonadotropins for 7 to 9 days per cycle, the multiple pregnancy rate is considerably less (12.9%) than in patients with longer treatment. The efficacy of treatment does not diminish with repeat-treatment cycles. (AM. J. 0BSTET. GYNECOL. 138:801, 1980.)

THE Pos sr B ILITY of inducing ovulation with human pituitary gonadotropin was first demonstrated by Gemzell and associates. 1 Shortly thereafter the use of human menopausal gonadotropin (hMG) in combination with human chorionic gonadotropin (hCG) was introduced for the treatment of infertility resulting from disorders of the ovarian-hypothalamic-pituitary From the Department of Obstetrics and Gynecology, Columbia University. College of Physicians and Surgeons. Receivedj!Jr publimtion March 17, 1980. Re1•imljuly 22, 1980. Accepted ]ulv 31, 1980. Reprint requests: Dr. R. jewelewicz, Department of Obstetrics and Gynecology, 630 West 168th St., New York, .Yew York i0032. 0002-'l~7H/R0/230H0!+07$00.70/0

©

1980 The C. V. Mosby Co.

axis. This therapy has now been used lor about 20 years with great success, particularlv after methods for monitoring estrogen levels as a means ot following the progression of the treatment were described by lttrich 2 and Brown and Beisher. 3 Several reviews of hMG/hCG treatment have been published. 4 ~ In 1972. we reported on 10 I patients who had been treated with hMG/hCG for 212 cycles. 7 The main objective of that study was to relate preovubtory estrogen levels to the incidence of successful pregnancies and complications such as ovarian hvperstimulation and multiple pregnancies. The present paper represents a review of aii treatment cycles given in this department to date, including those of the earlier years. The main consideration after 6

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Table I. First conception and delivery of first living child No. of

Group

patients treated

Group I (low gonadotropin levels)

109

First conception 69 (63.3%) 40 (45.4%)

88

Group 2 (normal gonadotropin

levels) Group 3 (elevated prolactin levels) Total

First successful ,bregnanr)' 60 (55.0%)

29 (32.99f,)

35

27 (77.1%)

26 (74.3%)

232

136 (58.6%)

115 (49.6%)*

*Among these 115 patients were 12 who after further treatment had another successful delivery of a second child (or children). One woman had two single children followed by quintuplets at a third delivery, and one woman was delivered twice of single children and twice of twins.

Table II. Ovulations and conceptions in 655 hMG/hCG treatments given to 232 patients No.

Conceptions

Group

of patients

Treatment cycles

".

109

320

304 (95%)

88

'lAO

C)AA /OQOJ:\

3

35

86

86 (100%)

Total

232

655

634 (96.8%)

""''"'

Ovulatory cycles

4""'X"'Y

this prolonged experience is to determine which groups of patients benefit most from this treatment and how long and which doses of hMG are optimal.

Material and methods Patient selection and classification. From 1963 to 1979, 242 patients were treated during 674 cycles. Among them were lO patients ( 13 cycles) with primary ovarian failure and high serum gonadotropin levels who did not respond as expected and were excluded from the following review. Included are nine patients with anovulation, with additional factors contributing to their infertility. Two had lysis of pelvic adhesions, two were treated for Asherman's syndrome, and five patients had husbands with low sperm counts. All patients except those with galactorrhea-amenorrhea were grouped according t(> the classification suggested by Insler and associates 8 and by the World Health Organization. Group I comprised 89 patients who had no evidence of estrogen activity and low serum gonadotropin levels. This group contained patients with hypogonadotropic hypogonadism, including 15 with primary amenorrhea. The patients presented with a history of amenorrhea, an atrophic vagina, absent or minimal cervical mucus, and absence of withdrawal bleeding after progesterone administration. Baseline estrogen levels were lower than 10 J.Lg/24 hours in the urine or lower than 80 pg/ml in the serum. Group 2 included 84 patients who had evidence of some endogenous estrogen activity and low or normal gonadotropin ieveis. These patients had a history of

\JU/V}

Anovulatory cycles 16 ~

(%

of ovulatory cycles) 90 (29.6%) AO /10.,.,01\

J

,-a \l.;:J.I !OJ

()

44 (51.2%)

21

182 (28.7%)

oligomenorrhea or amenorrhea for less than 6 months, demonstrated cervical mucus and an estrogenized vagina, and had withdrawal bleeding following progesterone administration. Baseline estrogen levels were higher than lO ~-tg/24 hours in the urine or greater than 80 pg/ml in the serum. When estrone and estradiol measurements were done separately, estrone was usually the major component. The majority of patients in this group were diagnosed as having the polycystic ovary syndrome. Because of the importance of prolactin in the reproductive processes and the ability to measure it in the blood, patients with the galactorrhea-amenorrhea syndrome formed a third group. The diagnosis was based on clinical observation of galactorrhea-amenorrhea and, since 1974, prolactin levels were determined in all anovulatory patients. Group 3 included 35 women. If previous treatment for pituitary adenomas by radiation or operation was successful, those patients were included in Group 1 and only those patients with persistent galactorrhea or elevated prolactin levels were included in Group 3. Mode of therapy. Pergonal was used as the hMG preparation in all patients. There is general agreement that the Pergonal administration schedule has to be adjusted individually. Since 1966, all of our patients have been started with two ampules of Pergonal daily (75 IU of follicle-stimulating hormone (FSH) and 75 IU of iuteinizing hormone (LH) per ampuie). The dose was then increased every 3 to 4 days as indicated by the ovarian response. The last dose of Pergonal was fol-

hMG and hCG for induction of ovulation

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Table III. Outcome of conceptions l olaf r:rn1Jh ~-·

~~r

f:nnrPhf1nl1\" ~---~--~r~~---~-·

Single pregnancies

J\1-ultiple pregnancies

42 (46.6%) 25 (52.1%) 24 (54.5%)

24 (26.7%) 7 (14.6%) 10 (22.7%)

91 (50.0%)

41 (22.5%)

:l

44

24 (26.7%) 16 (33.3%) 10 (22.7%)

Total

182

50 (27.5%)

:!

90 48

Abortions

lowed by a single dose of 10,000 IU ofhCG. The length of Pergonal therapy was usually 7 to 15 days but in individual cases it was extended up to 25 days. In patients treated before 1966. the treatment was more variable. particularly with respect to the dose of hCG. Estrogen monitoring of ovarian response. In a small group of patients who received hMG/hCG before 1964, the degree of ovarian response was judged by clinical impression only. Starting in 1964, measurement of urinary estrogens was used to monitor the response. A preovulatory urinary estrogen level of 80 to 250 /Lg/24 hours was considered to be adequate.' Since 1977, serum estrogen levels determined by radioimmunoassay have been used. Preovulatory serum estrogen levels in the range of !iOO to 1,500 pg/ml are considered optimal. Evidence of ovulation. Occurrence of pregnancy provided definite proof of ovulation. Blood progesterone levels above 3 ng/ml (or urinary pregnanediol levels above 2 mg/24 hours) and/or biphasic temperature curves together with appropriately timed uterine bleeding provided indirect evidence of apparent ovulation. Results

Among the 232 women treated for infertility, 136 conceived and 115 were delivered of living infants. The greatest percentage of successfully treated women was seen in Group 3 (74%); somewhat smaller success rates occurred in Group 1 (55%) and in Group 2 (33%). These data are shown in Table I. Among the 115 patients with successful pregnancies, after further treatment, 12 had another successful delivery of a second child (or children). (See footnote to Table !). The data on ovulation and conception for all treatment cycles arc shown in Table II. Ovulation was induced in nearly all treatment cycles. The ovulation rate (ovulations per treatment cycle) was between 95% and 100% in all three groups of patients. The conception rate achieved during these cycles was 51.2% in Group 3 (the patients with galactorrhea-amenorrhea), 29.6% in Group I, and 19.7% in Group 2. The conception rate

Group

I Twins

Tripiets

;vo. of lit•f births

nn

\73.3%> 32 (6n.fi%l 34 •.77.3'7<1

132 <72.50()

I Quadrupiets 1 Quintupiets

Totai

24

18

5

(i

! 4

(l

3

5 5

0

j()

Torai

28

j()

2

4i

2

7

was significantly higher (P < 0.00 l) in Group 3 than in Groups 1 and 2 and significantly lower ( P < 0.00 l) in Group 2 than in Group I. However, Group 2 excluded all women who had conceived following- clomiphene administration. If this portion of our patient population had been treated with hMG/hC<.~ instead of clomiphene. the conception rate in Group 2 might well have been higher. Table III presents the outcome of th<' IH2 conceptions. Successful pregnancies resulted in 132 patients (72.5%) while 50 pregnancies (27.5%) ended in abortion. Most of the abortions occurred in the lirst trimester and there were only a few in the second trimester. The abortion rate (as percent of conceptions) was slightly higher in Group 2 than in Groups 1 and ~t Among the successful pregnancies, 9 I. were single births and 41 were multiple births. The overall multiple-pregnancv rate was 31% of live births with a significantly lower percentage in Group 2 than in Groups 1 and 3 (P < 0.00 1). The breakdown of multiple pregnancies is shown in Table IV. There were 2H twins. 10 triplets, two quadruplets, and one set of quintuplets in our series. Table V presents the number of treatment cycles administered befi1re a patient achieved umception followed by a live birth. Of the 132 conceptions resulting in a living child 39.4% occurred after tht· first cycle. Women who desired repeat treatment after having a first child are included in this table as starting again with their first cvde. Up to 14 treatment cycles have been given to women who wished to continue treatment. However, a considerable number of patients chose to discontinue treatment at earlier stages, some even after the first or second cycle when these had not

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Table V. Number of treatment cycles required to achieve conception and a live birth Cycle 1 2 3 4 5 6 7 8 9

!0

No. of patients

Conceptions

242 163 87 49 32 21 12 9 6 2

74 47 23 11 10 4 5 3 3

Abortions

(30.6%) (28.8%) (26.4%) (22.4%) (31.2%) (19%) (41.6%) (33.3%) (50%)

Successful pregnancies

22 (9.1%) 10 (6.1%) 5 (5.7%) 3 (6.1%) 3 (9.4%) 2 (9.5%) 2 (16.6%) 1 (11.1%) 1 (16.7%)

52 37 18 8 7 2 3 2 2

(21.5%) (22.7%) (20.1%) (16.3%) (21.8%) (9.5%) (25%) (22.2%) (33.3%)

Discontinued treatment without live birth 27 39 20 9 4 5 6 1 2

!

11 12 13 14 Total

50

182

132

114

Table VI. Days of Pergonal treatment required to attain sufficient ovarian stimulation Days

No. of ovulatory cycles

Conceptions

Abortions

Live births (%of conceptions)

Multiple pregnancies (% of live births)

7-9 10-15 16-25

158 376 100

49 (31.0%) 107 (28.4%) 26 (26.0%)

18 (36.7%) 21 (19.6%) 11 (42.3%)

31 (63.3%) 86 (80.4%) 15 (57.7%)

4 (12.9%) 34 (39.5%) 3 (20.0%)

Table VII. Ampules of Pergonal given per ovulatory treatment cycle lVo.

No. of ampules 9-19 20-39 40-59 60+

of ireatrnent tycles

Group I 42 145 61 56

(13.8%) (47.6%) (20.1%) (18.4%)

Group 3 70 133 33 8

(28.7%) (54.5%) (13.5%) (3.3%)

6 41 24 15

(7.0%) (47.7%) (27.9%) (17.4%)

One ampule of Pergonal is equivalent to 75 IU of FSH plus 75 IU of LH.

resulted in pregnancy. These patients are listed in the last column of the table. The pregnancy rates suggest that the chances of conception and successful delivery do not decline significantly as the number of treatment cycles increases. Therefore, it appears justified to encourage patients to continue treatment, even beyond the first three cycles. Not only the dose of Pergonal but also the time span over which it was administered appeared to influence the outcome of treatment. Pergonal was given over 7 to 25 days before ovulation was induced. In Table VI the duration of treatment is grouped according to short (7 to 9 days), intermediate ( 10 to 15 days), and prolonged ( 16 to 25 days) periods. The intermediate period reflects most closely the physiologic period of follicular

maturation and it was this intermediate period which proved, in general, to be optimal. In this group the abortion rate was lowest, 19% as compared to 36% during the short and 42% during the prolonged treatment periods (P < 0.05). However, the incidence of multiple pregnancies was highest (39% versus 13% and 20%). The amount of Pergonal administered to an individual patient per cycle is shown in Table VII. Satisfactory response was elicited with 9 to 19 ampules in a considerable number of patients in Groups I and 2, but rarely in Group 3. The most frequently used dose was between 20 and 39 ampules. Practically all patients in Group 2 responded to up to 59 ampules, whereas a considerable number of patients in Groups I and 3 needed more than 60 ampules of Pergonal. Table VIII shows the extent of ovarian stimulation as judged by estrogen levels in blood or urine. The estrogen levels are grouped in such a way that the first group of the table represents levels corresponding to maximal midcycle physiologic levels, the second group represents levels found empirically to indicate ovarian stimulation optimal for induction of ovulation, and the third group represents extensive ovarian stimulation. While conception rates were similar in all three groups. the abortion rates were highest in the extensively stimulated group, a fact we reported eariier. 7 Consequently, the extensively stimulated group had 20% fewer sue-

hMG and hCG for induction of ovulation

Volume \3H :'\umber 7. Part I

805

Table VIII. Preovulatory estrogen levels and outcome of conceptions* Conceptions ,.~ \lrt1Un1 IP"t1Pl~

--~¥·

-...,~.¥

<150 J.tg/24 hr (urine) ../"~f\{). ~~.-/ ........

--...._;J\1\J

1 /\...1..-....--.....1\

P~/1111

(% of cycles)

¥----~

(%

Abortions of conceptions)

Live birth"\ conceptions)

I % of

:\1 ultiple pregrumries

I% of ln!f h1rths)

243

67 (27.6%)

16 (23.9°/il

'11 (76.1%)

l:l U5 :J'.:f)

185

56 (30.3%)

16 (28.6%)

40 (71.4%)

n

159

49 (30.8%)

21 (42.8%)

28 (51.2%)

10 n.r) 7'liJ

\UlU\..JU1

150-250 J.tg/24 hr (urine) 500-1,500 pg/ml (blood) >250 J.tg/24 hr (urine) >I ,500 pg/ml (blood)

1

~~U>'Jcl

*Blood levels on rlav of hCG: urine levels 1 to 2 days before hCG.

Table IX. Relationship between preovulatory estrogen levels and ovarian hyperstimulation Cycles without complication

Cycles with moderate hyperstimulation

< 150 J.tg/24 hr (urine) <500 pg/ml (blood)

239 (98.4%)

4 (1.6%)

()

150-250 J.tg/24 hr (urine) 500-1,500 pg/ml (blood)

180 (97.3%)

5 (2.7%)

I)

> 250 J.tg/24 hr (urine) > 1,500 pg/ml (blood)

123 (76.4%)

28 (17.9%)

8 (.'J'if-.)

·rota!

542 (92.3%)

37 (6.3%)

8 (!4%)

Estrogen leveL1

cessful pregnancies than the other two groups. The multiple-pregnancy rate was somewhat lower in the patients with preovulatory estrogen levels in the physiologic range (25.5% versus 32.5% and 35.7%). Of the 13 multiple gestations in this group, 11 were twins, one was triplets, and one was quintuplets. In the group with moderately elevated preovulatory estrogen levels, there were five twins, six triplets, and two quadruplets, and in the group with markedly elevated preovulatory estrogens there were eight twins and two triplets. In six of the 159 cycles in which excessive ovarian stimulation occurred, hCG was withheld in order not to induce ovulation. The incidence of hyperstimulation is analyzed in Table IX. In the majority of patients, no complications occurred, but in all treatment cycles 37 patients (6.3%) developed a moderate ovarian hyperstimulation syndrome, defined as ovarian enlargement of up to I 0 em. None required treatment. In eight cycles ( 1.4% of the treatments) severe hyperstimulation occurred, as defined by ovarian enlargement greater than 10 em and/or ascites and hydrothorax, and the patients were hospitalized for observation and treatment. No severe hyperstimulation occurred in patients with preovulatory urinary estrogen levels of less than 250 f.Lg/24 hours or serum estrogen levels of less than I ,500 pg/ml. Among the 132 live births, there were two newborn infants with congenital anomalies-one with multiple congenital anomalies and another with Down's syndrome.

Cvcles ;,•1fh severe hyperstimulation

Comment It is difficult to compare results of treatment with hMG-hCG among different investigators because of major differences in patient selection and the number of Pergonal treatment cycles given to an individual patient. Thompson and Hansen 1 summarized results from 100 investigators and found that 20% to 28% of patients conceived. Gemzell 6 reported that 'H.3f)t. conceived, and Spadoni and associates!) reported a 35.5C,f conception rate. A total of 58.6o/c of our patients conceived. There is also a marked difference in conception rates between groups of patients. The conception rate in Group l (63.3%) was higher than in Group 2 (45.4%), a finding consistent with results reported bi Oelsner and colleagues. 5 The main difference between Group I and Group 2 is that patients in Group 2 had been preselected: all of them had experienced failure of clomiphene. The combined conception rate in Group 2 would have been considerably higher if both clomiphene- and Pergonal-treated patients were included. Ellis 10 noted that the higher the basal e>trogen JeyeJs, the less successful the hMG treatment. High basal estrogen levels may be due to intraovarian pathology resulting from high local levels of androgens or to the presence of many follicles at various stages of maturation prior to treatment, some of which will be exhausted by the treatment while t.lw others will be tl!lderstimulated. The highest conception rate (77. I C() o<'curred in the

806

Schwartz et al.

Decemlwr I. )Ll/lll Am.

amenorrhea-galactorrhea group. Thompson and Hansen4 also noted better results in this group. The high prolactin level did not seem to increase the abortion rate by causing corpus luteum defects as might be expected. A significant observation was that the length of hMG treatment during the cycle had a significant bearing on the outcome of pregnancy. In patients given Pergonal for less than 9 days. the abortion rate was higher than in patients treated for a longer period of time. A possible explanation is that the follicle was immature, resulting in an abnormal corpus luteum. The multiple-pregnancy rate was significantly lower (12. 9%) in this group. perhaps because fewer follicles matured. The effectiveness of treatment does not diminish with repeated treatment cycles and the conception rate is about the same in the fifth treatment cycle as in the first. Therefore one may advise patients to continue therapy until pregnancy occurs if no other infertility problems are detected. The abortion rate in our patients was 27%, which is comparable to the 30% reported by Gemzell. 6 The abortion rate in spontaneously occurring pregnancies is under debate, making comparisons difficult. The reasons for the higher abortion rate reported in Pergonal-treated patients include the higher multiple-pregnancy rate and early diagnosis of pregnancy leading to recognition of very early abortion, which otherwise would have been missed. The data show that the abortion rate in Group 2 tended to be higher than in the other groups. In the patients with high preovulatory estrogen levels the abortion rate was significantly higher than in those with lower estrogen levels. A possible explanation is the formation of multiple corpora lutea that later degenerate, resulting in a marked decrease in the progesterone level in early pregnancy.

J.

Ohslet. (;, necq)

Our multiple pregnancy rate was 31%, almost the same as the 32.5% rate cited by Oelsner and cuworkers.5 There is a debate in the literature about the correlation between preovulatory estrogen levels and the multiple-pregnancy rate. Some authors 11 - 1'1 have found a relationship and they claim that lower preovulatory estrogen levels will reduce the rate of multiple gestations; however, the number of patients thev have presented is small. In a previous publication 7 and in agreement with others''· 14 we did not find a correlation. Our present data show only a slightly lower rate of multiple gestation in the group with preovulatory estrogen levels in the physiologic range. Eleven of the 13 multiple gestations in this group were twins. Since our first report of hyperstimulation syndrome in one of our patients, 15 we have bad seven additional patients with the syndrome who required hospitalization. The severe hyperstimulation rate was I. 4% of the total number of treatment cycles. In a review of the literature, Schenker and Weinstein 16 quoted the frequency of severe hyperstimulation as O.H% to 2%. Moderate hyperstimulation occurred in 6.3% of the treatment cycles. All of our patients recovered completely. In the majority of patients with extensive ovarian stimulation no complication occurred. Ovarian hyperstimulation can be prevented by withholding hCG administration in patients with high preovulatory estrogen levels. In conclusion, treatment with hMG-hCG for induction of ovulation is highly successful, and ~he complication rate is low. The recommended duration of treatment is 9 to lO days per treatment cycle. Treatment can be repeated if necessary in patients without other infertility problems.

REFERENCES 1. Gernzell, C. A., Diczfalusy, E. and Tillinger, G.: Clinical effect of human pituitary follicular stimulating hormone (FSH), J. Clin. Endocrinol. Metab. 18:1333, 1958. 2. Ittrich. G.: Untersuchungen iiber die extraktion die roten Kober-Farbstoffs durch organische Uisungsmittel zur ostro!!enbestim im Harm. Acta Endocrinol. (Copenh.) 35:34, 1960. . 3. Brown, J. B., and Beisher, N. A.: Current status of estrogen assay in gynecology and obstetrics, Obstet. Gynecol. Surv. 27:205, 1972. 4. Thompson, C. R., and Hansen, L. M.: Pergonal (menotropins): A summary of clinical experience in the induction of ovulation and pregnancy, Fertil. Steril. 21:844, 1970. 5. Oelsner, G., Serr, D. M., Mashiach, S., Blankenstein, J., 1

6.

7.

8.

9.

Snyder, ~vf., and Lunenfcld, B.: The study of induc_tion-of ovulation with menotropins: Analysis of results of 1897 treatment cycles, Fertil. Steril. 30:538, 1978. Gemzell, C.: Treatment of female and maie sterility with human gonadotropins, Acta Obstet. Gynecol. Scand. (Suppl.) 47: I, 1969. Jeweiewicz, R., Dyrenfurth, 1., Warren, M. P., and Vande Wiele, R. L.: Ovarian overstimulation syndrome, in Rosenberg, E., editor: Gonadotropin Therapy in Female Infertility, Amsterdam, 1973, Excerpta Medica, p. 235. Insler, V., Melmed, H .. Mashiach, S., Monselise, M., Lunenfeld, B., and Robau, E.: Functional classification of patients selected for gonadotropic therapy. Obstet. Gynecol. 32:620, 1968. Spadoni, L. R., Cox, D. W., and Smith, D. C.: Use of

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human menooausal g:onadotrooin for induction of ovulation. A.M. J 'ossTE,;:'. GYNECO~. 120:988, 1974. 10. Ellis. J. D.: Factors influencing the pregnancy and complication rates "vith human menopausal gonadotropin therapy. Br. J. Obstet. Gynaecol. 82:52, 1975. II. Taymor, M. L., Yussman, M.A., and Gminski, D.: Estrogen monitoring in ovulation induction, Fertii. Sterii. 21:759, 1970. 12. Karam. K., Tavmor, M. L., and Berger. M. T.: Estrogen monitoring an·d prevention of ovarian ove~stimulauon during gonadotropin therapy. AM. J. OssTET. GYNECOL. 115:972. i'l7:~.

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13. Notation, A. D., Ta~ratz, G. E., and Stern·s, \I. W .: Serum 17-beta-estradiol ir{dex of follicular maturation during gonadotropin therapy, Obstet. Gynecol. 51:204, l~J71:L . 14. \A/u, C. H.: Plasma hormones in human 1-{0nadotropin

induced ovulation, Obstet. Gvnecol. 49:30H. 1970. 15. Neuwirth, S. R.. Turksoy. N. ·R., and Vandt• Wiele. R. L.: Acute Meig's syndrome secondary to ovarian stimulation with human menopausal gonadotropins, :\ vr. .I· Ossn r. GYNECO!.. 91:977, 1963. 16. Schenker. J G .. and Weinstein, D.: Ovari;tn hyperstimulation syndrome: A current survev, Fcrtil. '-'tnil. 30::.!:.!'1. 197H. . .