Clomiphene citrate for improvement of ovarian function

Clomiphene citrate for improvement of ovarian function GEORGEANNA MARIA Baltimore,

SEEGAR D.

DE

JONES,

MORAES-RUEHSEN.

M.D. M.D.

Maryland

Clomiphene citrate was used in a group of patients with various forms of ovarian dysfunction: 6 so-called “normal infertile females,” 9 women with luteal phase defects, 56 with oligomenorrhea and anovulation, 4 with lactation amenorrhea, 10 with primary amenorrhea, and 7 with “unresponsive ovarie.s? Ovarian function was estimated by basal body temperature, endometrial biopsy, and urinary excretion of estrogens and pregnanediol. Pregnancies were followed with urinary pregnanediol and serum chorionic gonadotropin titers. Previously normal ovarian function became abnormal after 450 mg. of clomiphene citrate. Anovulation not associated with severe pituitary insufficiency was corrected in all patients by 250 to 500 mg. of clomiphene citrate, and smaller dosages seemed more effective than larger. Luteal phase defects following induced ovulation were significantly higher than in a series of patients with spontaneous ooulatory function.

A G R o u P of 91 women have been treated with clomiphene citrate to determine its effect upon ovarian function under various physiologic and pathologic conditions. The efficacy of altering the amount of drug given, as well as the duration of administration has been assessed by estimating ovarian estrogen and progesterone production. If, and when, pregnancy occurred, serum chorionic gonadotropin values and urinary pregnanediol assays were made in an effort to determine factors which might predispose to abortion. This is of importance as those pregnancies following induction of ovulation by clomiphene citrate have been reported to be associated with a high incidence of miscarriage.’

be psychogenic or neurogenic in origin (this group included th ose patients with the SteinLeventhal syndrome) ; 4 patients with “post oral contraception amenorrhea” of more than one year’s duration; 6 patients with dysfunctional uterine bleeding of the anovulatory variety thought to be neurogenic in origin. Four patients had lactation amenorrhea: 2 of these had the classic Chiari-Frommel syndrome following pregnancy, but there was minimal x-ray evidence of pituitary tumors; 2 had the Ahumada-de1 Castillo syndrome with amenorrhea and lactation unassociated with a previous pregnancy. One of these also had minimal evidence of pituitary tumor while the other did not. Four patients had long-standing amenorrhea with evidence of severe gonadotropic deficiencies all presumably psychogenic in origin. Ten patients were treated who had primary amenorrhea. Of these. two had hypogonadotropic eunuchoidism, 3 had a delayed puberty syndrome, and 5 are unexplained etiologically. Seven patients had evidence of an unresponsive ovary ; 4 of these eventually were shown to have premature o\:arian failure

Clinical material The clinical material studied consisted of six apparently normal women with unexplained infertility and nine women with normal ovulation but deficient luteal function: 42 women with oligo- or amenorrhea said to Prom the Departments Gynecology, The Johns and The Johns Hopkins

of Obstetrics and Hopkins Hospital University. 814

Volume Number

99 Ii

Clomiphene

and one has been demonstrated to have the unusual syndrome of psychogenic amenorrhea with elevated gonadotropins described by Rakoff.” The remaining 2 patients are thought to have this same syndrome but it has not been diagnosed by ovarian biopsy. Because none of the 7 responded to therapy, they will not be discussed in this paper. Methods All patients were investigated for the etiology of the anovulation.3-” The ovarian estrogen and progesterone production levels were assessed by urinary estrogen assays using the technique of Brown and Matthew,” urinary pregnanediol assays by the technique of Jones and associates,7 serial vaginal smears using the Davis pipette and evaluated as previously described by de Moraes-Ruehsen and Masukawa,8 and endometrial biopsy interpreted according to the criteria of Noyes, Hertig, and Rock” in association with the basal body temperature chart.

ESTROGENS PREGNANEDI _- - --. -- PI

citrate

and

ovarian

function

Results Normal cycles. The 6 apparently normal women with unexplained infertility were given increasing amounts of clomiphene citrate beginning on the fifth cycle day, dosages ranging from 50 mg. a day for 3 days to 450 mg. over a 3 day period, given as 200 mg., 200 mg., and 50 mg. on the third day. The higher dosages were almost invariably associated with increased estrogen excretion. Three of 4 patients who received 450 mg. in 3 days had estrogen values of over 100 pg per 24 hours, which is above the normal cycle range. The endometrial biopsy patterns which had been normal prior to therapy became abnormal with the higher dosage levels in 3 of 4 patients studied (Fig. 1). The administration of 50 mg. of clomiphene for 3 days beginning on the fifth cycle day did not seem to change the ovarian function in any of the 6 patients as judged by the parameters used in this study. All 6 patients were exposed to pregnancy

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Fig. 1A. Basal temperature record of a “normal” infertile woman with a normal luteal span. Pyknotic index, urinary estrogens and pregnanediol excretion within limits. Endometrial biopsy in phase.

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patient after clomiphene treatment. Basal temperature record is deficient. with a short 11 day luteal phase. Endometrial biopsy taken on thr twenty-third cyclr day had a histology compatible with an t 8 day pattern Same

during the course of their clomiphene administration. Four received six courses of clomiphene and one patient received onI> one course ; none of these patients became pregnant. The sixth patient, however, became pregnant on her third course of clomiphene therapy in which she had received 50 mg. of drug for 5 days. This patient had an impotent husband and the pregnancy was thought to have resulted from homologous insemination rather than drug administration. Discussion and conclusions. From this admittedIy small group of patients, it was concluded that short high dosages of clomiphene citrate given within the first week of a normal menstrual cycle would increase the estrogen production and, by inference, theoretically thereby increase the number of develcping follicles and the probabiIity of multiple

ovulation. Early in the cycle clomiphene apparently does not interfere with ovulation, although if given one to 7 days prior to expected ovulation, Whitelawl” has demonstrated that ovulation can be delayed and the luteal phase prolonged. There is no indication from the present series that the socalled normal infertile couple will have an improved pregnancy rate following the administration of clomiphene citrate, at least in the manner in which it was given here. LuteaI defect. Nine women with luteal phase defects diagnosed by two or more timed endometrial biopsies showing a histologic pattern 2 or more days behind the anticipated pattern according to the onset of menses also received clomiphene citrate. The scheme of treatment in this group was similar to the one used in the “normal cycle,” except for a patient with a severe lu-

Volume Numbet-

99 6

Clomiphene

citrate

and

ovarian

function

817

A Fig. 2A. Fairly regular cyclic bleeding in a woman (M. F.) with severe luteal phase defect (aluteal cycle). Clomipbene citrate in various dosage schemes improved but did not correct the luteal dysfunction. S = stroma; G = glands of endometrium.

Fig. 28. Endometrial proliferative pattern

biopsy in the same patient taken in an untreated cycle. (Hematoxylin

on the twenty-third and eosin. x100.)

cycle

day showing

a

818

Jones

and

Moraes-Ruehsen

Am.

Fig. 3. A, Endometrial biopsy of M. F. after a course of clomiphene citrate (50 day for 5 days). It was taken on the first day of bleeding and was read as 20-21 metrium. There is also some histologic glandular reduplication associated with amount of secretion. (Hematoxylin and eosin. x200.) B, Endometrial biopsy taken same patient after the administration of a longer clomiphene course (50 mg. every 10 days). It was obtained on the twenty-sixth cycle day. There is also histologic the glands show the subnuclear vacuolization of the 16-17 day pattern and the still compact. (Hematoxylin and eosin. x200.)

Novrmbrr J. Obst.

mg. day

15. & G

every endoa good from the day for disparity: stroma is

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A

E = ESTROGEN P = PREGNANEDIOL

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24 HRS. mg./24

citrate

and

ovarian

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6 Pig. 4. A, Pyknotic index (- - - -) of a patient with luteal phase defect an the 14th cycle day, although there is no consistent temperature rise, Estrogens (E) and pregnanediol (P) excretion are abnormally low. B, Basal c’rd, pyknotic index, and urinary steroid excretion in the same patient citrate treatment. Symbols as above. Note the improvement of estrogens titers. The patient conceived during this cycle. C.G. = serum chorionic

teal phase defect who received a 10 day course (Figs. 2 and 3). Three of the 9 seemed to show a correction of their luteal defect and two of these three became pregnant; the other discontinued therapy after four ovulations. Two other patients showed some improvement in their luteal function. The remaining 4 women showed no substantial laboratory or clinical improvement. Two of these patients subsequently were treated. with substitution progesterone therapy a:nd promptly became pregnant; the

suggests ovulation (---) afterward. temperature recafter clomiphene and pregnanediol gonadotropin.

other 2 have withdrawn from the treatment series. Discussion and conclusions. Theoretically, clomiphene citrate would be of value in the treatment of a luteal phase defect if it were associated with a relatively poor estrogen milieu, as classically illustrated (Fig. 4). This etiology for a luteal phase defect, however, is in our experience very unusual and the more common cause is a deficiency of progesterone related to a defective pituitary LH. As illustrated by 2 patients who be-

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came pregnant with progesteroncb slthstitti. tion therapy immediatelv after a 6 montt~ trial of clomiphene, t ht. administration oi clomiphene citrate apparently will not carrect. the inability of thr patient’s own pituitary to produce an LH flood. Although those patients who have severe defects (as illustrated in Fig. 2 I do show some improvement with clomiphene, theoreticall) because their estrogen flood becomes more> adequate, they nevertheless require some additional LH supplementation. Progesterone substitution therapy seems a much simpler procedure for correction of the luteal phase defect and is unassociated with the risk of multiple pregnancies. Oligoor amenorrhea of psychogenic or neurogenic origin apparently associated with a specific FSH deficiency and no-ma1 LH potential as evidenced by normal urinary gonadotropins and some estrogenic function. There were 42 women in this category clinically characterized by oligomenorrhea OI amenorrhea of relatively short duration and thought to have a psychogenic or neurogenic ‘gin. The Stein-Leventhal syndrome is currently classified as a hypothalamic disturbancc and 17 patients with this syndrome have been included.” Six had had previous wedge resection operations whictl failed. Thirty-nine of the 42 patients ovulated on either 50 mg. of clomiphene citrate fot 3 days or 5 days. The remaining 3 patients were classified as partially resistant in that they required higher or more prolonged dosages of clomiphene citrate, 50 mg. daily for 10 days or 100 rng. daily for 5 days. All of these patients continued to show a consistent response to therapy throughout the duration of their treatment. Only one patient received more than six therapy cycles. Seventeen women among the 36 patients achieved 18 pregnancies; however, 3 women had infertile husbands and 3 had associated tubal occlusion, while an additional patient had only one ovulatory cycle before withdrawing from therapy. Of the remaining 12 women who failed to achieve a pregnancy, 7 had severe luteal dcftscts. Two patients

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had cm$ :‘I and 4 IJ\ ulations. resprctivel). before withdrawing from thr series. In addition. thcsc, patients wert’ treated fxarly in the series ad were giLen 50 111g. of clomiphene citrate daily for 10 days. One patient has been under therapy less than 3 months: the other 2 cases are unexplained. ‘I’here \\crch 6 abortions. I5 ttlrnl pregnancies, and 3 patients art’ currently pregnant. Three of thcx 6 abortions were associated with luteal phase defects and an additional 3 pregnancies had demonstrable luteal phase defects as diagnosed by deficient pregnanediol (LXcretion, but the pregnancies progressed to term with therapy. One pregnancy which aborted without an associated luteal phase was a blighted ovum with associated abnormal chorionic gonadotropin. This patient had had an unexplained fever at the timt of ovulation and this was interpreted as the etiologic factor; another had myomas of the uterus and aborted a grossly normal fetus at 5 months. ‘I’herc were 2 twin pregnancies among tht> !I term deliveries. One occurred in a patient with a Stein-Leventhal syndrome who had received 50 rng. of clomiphenr citrate for 10 days. ‘I’hr other patient had psychogenic amenorrhea. and had received 50 1;~. 01’ c,lomiphenr citrak daily for only 3 days. Post oral contraception amenorrhea. There werp 4 women with long-standing amenorrhea following oral contraception therapy. All 4 of these patients ovulated. although one was partially resistant, giving a very poor lutral phase after ovulation. Two of the -t patients conceived and are currently pregnant. Anovulatory dysfunctional bleeding. Six women with anovulatory dysfunctional uterine bleeding were treated (Fig. 5). These patients required more prolonged therap) for an ovulatory response. One patient did not ovulate following a single course of 50 mg. of clomiphene citrate for 10 days. Of the remaining 5, 4 did ovulate and the fifth apparently had aluteal cycles.‘” Her basal temperature chart, endometrial biopsy, and urinary precnanediol 1~~1 failed to indicate

Clomiphene

citrate

and

ovarian

function

Fig. 5. A, Endometrial biopsy taken in a patient with dysfunctional uterine bleeding. The histology is compatible with benign endometrial hyperplasia. (Hematoxylin and eosin. x500.) B, Endometrial biopsy of the patient after 15 days of 50 mg. of clomiphene citrate. The !glands still have the subnuclear vacuolization of the 17-18 day pattern; the stroma alread) shows beginning of pseudodecidual reaction compatible with a 23 day pattern. (Hematoxylin and eosin. x200.)

82’

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oligo-

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Hypothalamic ovulation

Hypothalamic ovulation

C. J.

E. H.

M. S.

s. L. (2)

H. G.

15

16

171

18

19

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daily.

(50

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oligo-

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231

first

Hypothalamic ovulation

M. C.

22

“Progesterone

Psychogenic rhea

S. M.

21

Hypothalamic ovulation

Stein-Leventhal syndrome

R. M.

20

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initially.

20

24

23

28

oligo-

Hypothalamic ovulation

L. A.

20

25

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29

28

23

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amenor-

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12

Table I-Cont’d

S.L.

followed (2)

33

38

39

36

74

35

33 49 96

49 184 229

36 86 107

43 166

pr-e.qancy-low

17-hydroxyprogesterone

second

by

21-22

23-24

23-24

22-23

25-26

17-18

25-26

24-25

23-24

18-19

pregnanediol

capmate

5.9

1.2

5.4

1.0

7.1

3.2

2.9 1.9 3.6

4.0 0 3.2

4.1 1.5 6.9

4.3 22.5

assay.

(125

weekly. Pregnancy

mg.)

33

38

39

36

33 50

33 49

49 57

36

33 43

is proglessina

1,230

7,050

11,450

2,425

1,800 16,000

1,140 70,400

19,952 30,700

1,050

1,340 25,800

normally

on

None

None

Yes

Yes

Yes

None

Yes

Yes

Yes

Yes

Yes

Yes

therapy.

Abortion

.4bortion-

Abortion--l2

Abortion---l6 No fetus

-7 weeks

-8 weeks

weeks

weeks.

Abortion-20 weeks. Normal female fetus

Abortion-2 Normal

Current

Current

1 weeks. female fetus

male

Term normal infant

Current

female

female

Term normal infant

Term normal infant

w w

n 9

824

Jones

ond

Moraes-Ruehsen

ovulation; however, her menstrual cycle was regular and not profuse. One of the 3 married women conceived. Discussion and conclusions. Ovulation can be induced by clomiphene citrate in practically all patients with amenorrhea or oligomenorrhea due to psychogenic or neurogenic factors with evidence of mild pituitary insufficiency, probably characterized by an FSH deficiency and a normal LH control mechanism as evidenced by detectable ovarian estrogen production. The dosage does not need to be excessive (over 250 mg.) and there is some evidence that smaller dosages are more successful and produce more nearly normal ovarian function than iarger dosages. Additional experience by Roy and associatesI would seem to substantiate these findings. The group of patients with anovulatory dysfunctional uterine bleeding, however, seemed to require a somewhat more prolonged administration and a higher dosage (500 mg.) . The cause for this is currently not obvious but may indicate a primary ovarian etiology. Those patients with a hypothalamic suppression from oral contraception responded well. Forty-three patients were married and 20 became pregnant. Seven of the 23 women who failed to conceive had additional factors which accounted for this; 4 because of male infertility and 3 because of tubal occlusion. Six are still under too short a period of therapy for complete evaluation, e.g., less than six cycles. Eight additional women who failed to conceive showed gross abnormalities of the luteal phase, which is interpreted as a contributing factor for the infertility. Further substantiation for the role of the luteal phase defect in the etiology of infertility is gained by the abortion rate among the patients who conceived. There were 6 miscarriages, 3 of which were associated with inadequate progesterone production, and an additional 3 patients showing inadequate progesterone were carried to term on early progestational therapy (Table I). The unusual number of luteal phase defects in this series indicates ‘to us that in addition to a FSH defect many of these patients have

November 15, 1967 Am. J. Obat. & Gyner.

inadequate LH stimulation which is not completely corrected by clomiphene citrate. Severe pituitary insufficiency. There were 18 patients with evidence of severe pituitary insufficiency. Four had amenorrhea of longstanding, thought to be psychogenic in origin. Ten had primary amenorrhea; 3 were young individuals, under 18 years of age, thought to have delayed puberty; 2 were older individuals with hypogonadotropic eunuchoidism. Five cases were of undetermined etiology. Four had lactation amenorrhea; 2 of these had the Chiari-Frommel syndrome and 2 had the Ahumada-de1 Castillo syndrome. Of the 18 patients in this entire series, only 6 ovulated. Two of these 6 women were married, but neither conceived. Four of the 6 patients who did ovulate were partially resistant and showed severe luteal phase defects. Two patients in the delayed puberty group who responded to the drug consistently were not tested for luteal deficiencies. Discussion and conclusions. Patients with hypogonadotropic eunuchoidism, as well as those with lactation amenorrhea, failed to ovulate even when given clomiphene citrate over long periods of time, e.g., up to 50 to 100 mg. daily for 30 to 60 days; however, they excreted large amounts of estrogen. This, together with evidence of marked luteal defects among those patients who did ovulate, would suggest that these patients are deficient in their ability to respond to an estrogen stimulus by a flood of pituitary LH. If a lutein stimulator, HCG, is given at the proper time, ovulation can be induced. These patients will be reported upon in detail elsewhere. Although ovulation has been induced in patients with the Chiari-Frommel syndrome using clomiphene,l” this and any form of lactation amenorrhea should be suspected of being due to a pituitary or neurogenic tumor. Therefore, such patients should be periodically reinvestigated with this diagnosis in mind. Side effects and complications. Although when used in low dosages over short periods of time, e.g., not over 100 mg. daily for 5

Volume Numhcr

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days, few, if any, side effects are seen. Clomiphene is, nevertheless, metabolized in the liver and patients with liver disease should be excluded from such therapy.l In addition, perhaps prior to treatment, patients who have a history of past liver disease should have liver function tests. The most frequent side efect noted has been the hot flush. One patient in the present series exhibited characteristic signs of an allergic reaction with rash and fever. .4t high dosage, vertigo and peculiar visual disturbances, usually characterized by blurring and rainbow vision, are occasionally encountered. Nausea is rare. The two serious complications associated are multiple ovulations and multiple pregnancies,. The production of enlarged cystic ovaries with multiple ovulations can result in death from rupture and hemorrhage or be associated with severe complications, such a!, ascites and pleural effusionlB or serious thromboses”‘; both results were reported following multiple ovulations with human menopausal gonadotropin. In spite of the theoretically lower chances of the over-stimulation syndrome with clomiphene citrate than with human menopausal gonadotropin, one such case has been described.l’ Usually, if drug dosage has not been excessive or accompanied by an additional luteal stimulator, such cysts will regress spontaneously under conservative therapy of bed rest and observation. Occasionally, however, operative intervention with aspiration of the cyst is necessary. Ovariectomy under these circumstances is contraindicated. In the present series only 6 patients had palpable ovarian cysts with minor abdominal discomfort and hospitalization was not required. If multiple ovulations occur, multiple pregnancies can be anticipated, and 10 to 15 per cent of all pregnancies induced by clomiphene have been multip1e.l Although the majority of these have been twin pregnancies, triplets and quintuplets have also occurred. The increased medical hazard to the mother, as well as the fetus, makes this eventuality something less than a medical success. In addition, one must consider the

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financial handicaps imposed by such multiple births, as well as the difficulty in successfully raising such babies to be well-adjusted individuals. Although the dosage as well as the etiology of the anovulatory defect do seem to play some role in the induction of multiple ovulations and pregnancies, at present one cannot predict absolutely the conditions which predispose. Therefore, each patient must be carefully acquainted with the possibility and the lowest possible dosage used in an effort to preclude such complications. Patients with polycystic ovaries are in the high-risk group, apparently because they have large amounts of endogenous gonadotr0pins.l” The ovary, therefore, has numerous follicles already partially stimulated and prepared for ovulation. Recently it has been our practice to ask patients with this complication to use some form of precaution against pregnancy in the first induced ovulation. Theoretically, the excessive follicles will be ovulated and the second course of therapy will have less chance of superovulation. There is as yet too little information to evaluate the efficacy of this approach. Comment

To be used most effectively and with the fewest possible complications, the physiologic action of clomiphene citrate must be understood. Most, if not all, of its activity can satisfactorily be explained on the basis of its action as a competitive estrogen inhibitor. Acting at the hypothalamic level it washes out the estrogen effect, thereby releasing the hypothalamic factors which influence pituitary gonadotropin secretion. There are four hypothalamic centers which secrete factors concerned with gonadotropin output: ( 1) the follicle-stimulating release factor (FSH-RF), which causes increased FSH pituitary production18 and which is classically inhibited by estrogens; (2) the so-called cyclic LH release factor which is operational only in the female and apparently permanently blocked in the male by androgen.“’ It is this center in the female which apparently responds to the estrogen

826

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flood. This action can bc easily understood if it is regarded as an inhibitory nuclvuhblocking LH release which in turn is inhibited by a high estrogen level: (3) the. tonic LH release factor (LH-RF) ,‘I whicll is apparently inhibited by progesterone; and 14 I the prolactin inhibitory factor (PIF 1. which can be blocked by chlorpromazinrs and related drqs,“’ but the physiologic control of which is really not understood. When this center is inhibited the pituitary productbs prolactin which in turn inhibits pituitary FSH and LH. It seems that estrogen in higlt dosage blocks all of the hypothalamic xonadotropic control centers. If then estrogen is the major physiologic blocking agent in the hypothalamus and clomiphene is a competitive estrogen inhibitor, it is thereby able to abolish the estrogen inhibition and allow the release factors to stimulate pituitary hormone secretion. As the FSH release factor nucleus is the major one affected by estrogen, it is this nucleus which is most affected by clomiphenc. Clomiphene, in the presence of an intact hypothalamus, an intact pituitary, and an ovary which is capable of being stimulated. can produce increased FSH-RF, stimulating pituitary FSH and causing ovarian follicle growth. The associated increased estrogen secretion occurs theoretically because of the presence of small amounts of LH. The estrogen flood causes a secondary LH flood through its effect on the cyclic LH release nucleus. However, if the hypothalamus is incapable of responding or the pituitary fails to produce an LH flood. clomiphene is unable to induce ovulation, as it apparently does not usually specifically induce an LHRF stimulation. Work by Boon and Schalch,‘” using a serum radioimmunoassay for LH, showed an immediate rise in LH of about half the magnitude of that which occurs later and immediately prior to ovulation, indicating that there is perhaps some stimulation to the LH-RF. Bardin, Ross, and Lipsett2* likewise found an increase in LH when clomiphene was administered to 15 normal men with intact

In addition, there is SOIIN* laboratory I’\ idencrl which indicates that the production of both FSH and, to a Imsrr dc,qrt:tt, LIf i> enhanced bv clomiphenr adrriinist~~atiorl. With this in mind. an etiologic diagnosis of every patient who is to be considered for clomiphenr therapy ia of utmost irnportanc~~. It has been said repeatedly in tht* litt~raturr that those patients who ha\,? detrctablr urinary ,gonadotropins and evidence of t’strogen production are the* ones who will IYspond. These are the patients who do havt’ some evidence of pituitary LH secretion. It is obvious that patients with primary ovarian failure, as in the pure gonadal dysgenesis 01 premature menopause, and patients with ovarian nroplasms must be excluded. Patients with severe psychiatric disturbances should be excluded as well as those with pituitary or intract,anial tumors. Patients with specif-ic causes for their anovulation (such as chronic nutritional deficiencies, especially if associated with psychiatric disturbancrs: anorexia nerlrosa; chronic illnesses: metabolic diseases, such as thyroid disturbances, adrenal hyperplasia. and adenomas, ar \vell as diabetes i should k~ treated specifically. The micirnal investigation should include an x-ray of the sella turcica and/‘or visual field ; a total urinary gonadntropin, 01‘ preferably fractionated serum gonadotropins, for LH and FSH, and hematocrit, white blood count, difrerential. and sedimentation rate studirs. Vqginal smears for maturation index and cancer cytology should be done. A urinar) estrogen assay, although \raluable, is tlot indispensable. If infertility is a major problem. the minimal diagnostic survey should he made: a semen analysis, tubal function test, Huhner test. basal temperature record, and endometrial biopsy at onset of menses if the patient is having menstrual function at all. The importance of the initial pelvic examination and repeated pelvic examinations throughout therapy cannot be too greatly emphasized. The esamination should ht. made immediately prior to initiating thrr-

Clomiphene

apy andi at weekly intervals during the first course. It is wise to begin the first course of therapy after an induction of withdrawal bleeding by progesterone. This will not only preclude the possibility of giving clomiphene to a pregnant patient, but also will suppress the hypothalamic LH-RF, thereby reducing the endogenous LH and the possibility of ovarian cyst formation. If pregnancy eventuates, a careful evaluation for a multiple pregnancy and adequacy of luteal function should be made. After the diagnostic survey and pelvic examination, the next important consideration is dosage. It has been found that a smaller dosage is more successful therapeutically and associated with fewer complications. Therefo’re, it is obvious that the smallest dose should be tried initially. The smallest dosage used in the present series was 50 mg. of clomiphene daily for 3 days, and even wi.th this low dosage one set of twins was induced. There is some indication that with increasing dosage there is increased estrogen production, indicative of increased follicle stimulation. If this estrogen induction is excessive in relation to the progesterone produced by the corpus luteum, an inadequate luteal phase can result because of the estrogen: progesterone disproportion. Occasionally, patients, particularly those who have dysfunctional uterine bleeding, will nevertheless require rather prolonged treatment. The 6 patients in the present series who were in. this category all required at least 10 days of therapy with 50 mg. of Clomid daily. Patients who have resistant syndromes indicating LH failure require marked individualization of therapy. An abnormality of the luteal phase was noted in 19 of the 56 patients who ovulated and may account for

REFERENCES

1. Johnson, J. E., Jr.: Pacific Med. & Surg. 74: 153, 1966. 2. Rakoff, A. E.: Fertil. & Steril. 4: 263, 1953. 3. Jones, G. E. S., and Nalley, W. B.: Fertil. & Steril. 10: 461, 1959.

citrate

and

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function

827

some of the failures of pregnancy to occur, as well as the relatively high rate of miscarriage. Conclusions

Clomiphene citrate is a valuable adjunct in the treatment of anovulation of hypothalamic origin. It is especially successful when the FSH-RF is depressed and the LH control centers are intact. A potentially normal pituitary and ovary are prerequisites for successful treatment; therefore, destructive lesions of either the pituitary or ovary should be carefully excIuded. Serious illness and metabolic disease, as well as serious psychogenic illness, should also be contraindications to clomiphene administration, as pregnancy under these conditions is contraindicated. Patients who are ovulating are not candidates for clomiphene therapy and probably constitute a high-risk group for the induction of multiple ovulations and multiple pregnancies.23 There is no rationale for treating the so-called “normal infertile couple” with this drug, and the results in our group of patients have substantiated this. The luteal phase defect, it would also seem, is not best treated with clomiphene citrate. In properly selected patients, ovulation can be induced in practically all patients and approximately half will achieve pregnancy if all other fertility factors are normal. The relatively low pregnancy rate may be related to the luteal phase defect, which occurs following many of these induced ovulations. The serious complications of multiple ovulations and multiple pregnancies can best be avoided by treating only those patients who have low endogenous gonadotropin production and by using the lowest dosage commensurate with ovulation in the individual patients being treated.

4.

Jones, G. E. S., and de Moraes-Ruehsen, M. D.: Fertil. & Steril. 16: 461, 1965. 5. de Moraes-Ruehsen, M., and Jones, G. E. S.: Fertil. & Steril. In press. 6. Brown, J. B., and Matthew, G. D.: Recent Prog. Hormone Res. 18: 337, 1962.

828

7.

8. 9. 10. 11. 12. 13.

14. 15.

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November 15, 1967 Am. J. Obst. & Gynw.

Moraes-Ruehsen

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