CLINICAL OBSERVATIONS ON CLOMIPHENE AND HMG

BY EDWARD T. TYLER, M.D.*
*Medical Director, Los Angeles Planned Parenthood Center, Los Angeles, California

Reprinted from "Advances in Planned Parenthood," Proceedings of the Annual Meeting of the American Association of Planned Parenthood Physicians, April 29 and 30, 1964

INVESTIGATIONS of products which induce ovulation have revealed that species-specificity is apparently required, and many preparations of gonadotrophins from sheep, bulls, and other animals have had to be discarded. In the past few years, extremely potent preparations have become available. These preparations, their physiology, and what can be expected from them will be discussed in this paper.
About seven years ago, Dr. R. Kistner of Boston got encouraging results from a new antiestrogen, a triphenylethanol compound, MER-25, a product of the William S. Merrell Co.; he was treating metastases from cancer of the breast, and tried MER-25 at the suggestion of Dr. Robert McMaster of the Merrell Company. It was thought that the compound had caused a temporary suppression of estrogens and had thus inhibited estrogenic stimulation of malignant tissue.

About a month later, the author developed the concept that estrogen antagonism could increase gonadotrophic function as a result of the reciprocal relation and, therefore, started to use MER-25 to induce ovulation. This theoretical approach, surprisingly, proved to be effective, even in some cases of secondary amenorrhea with long anovulatory intervals. The preliminary findings were presented for the first time (with guarded enthusiasm) at the International Fertility Association Meeting in Amsterdam in 1959(1) but in such a way as not to attract much attention. Subsequently, MER-25 proved markedly toxic, with a definite tendency to produce incidents of insomnia, severe agitation, and even psychosis. There was also a question of liver toxicity. The Food and Drug Administration (FDA) has since forbidden the clinical testing of the compound.

Nevertheless, it seemed apparent that this approach did lead to the induction of ovulation and it was decided to experiment with certain MER-25 analogues. Within a year, attention focussed on MRL-41, clomiphene, another compound in the series. Early in the study, the author, concentrating on possible contraceptive effectiveness, determined that in spite of some evidence to the contrary in animal experiments(2) neither MRL-41 nor MER-25 had any contraceptive action in humans. The original theory was that these compounds acted through their antiestrogenic properties, but in recent years different theories have been evolved. Greenblatt, who subsequently used this therapy extensively(3) has claimed FSH (follicle-stimulating hormone) function for clomiphene, but the author suggests a different mechanism of action as will be indicated in this paper.

Clomiphene therapy

Infertility patients with evidence of follicular activity and with cervical mucus of good amount and quality have been given MRL-41 with considerable success, i.e., ovulation has been induced as proved by occurrence of pregnancy. The estrogenic activity from the developing follicle demonstrates the presence of FSH, which the author considers essential to clomiphene effectiveness. If there is no evidence of a developing follicle, clomiphene is inadequate to produce ovulation.

Few good criteria are known for the certain diagnosis of ovulation. One of the best of the practical methods is pregnanediol determination, which can be done by having the patient collect urine for 12 hours overnight for 10 nights and then pooling the entire amount. Values between 3 mg. and 6 mg. in 24 hours are considered normal; and values below one mg. in 24 hours, on the basis of an average for the 10 days, are considered as evidence of lack of ovulation.

In some situations MRL-41 may produce ovulation with a poor secretory response and a short luteal phase. The luteal phase can be prolonged, however, by continuing medication for a longer period than recommended or by supplementing it with chorionic gonadotrophin. Another type of reaction which may occur after clomiphene therapy is a very abbreviated temperature rise with some evidence of secretory effect. Culdoscopies performed in these patients indicate that the reaction represents luteinization of unruptured follicles, a useless effect but one that is not infrequent.

In one case of secondary amenorrhea and anovulatory cycles, the patient was given medication for a longer period than usual with the result that she developed considerable abdominal distress and surgery became necessary. This woman had ruptured ovarian cysts bilaterally. The pathological findings indicated that the cysts were for the most part corpus luteum cysts, which seemed to indicate that clomiphene has a strong LH (luteinizing hormone) effect, and that large amounts can produce ovarian pathology.

Clomiphene action

On the basis of observations made so far, it appears that the basic action of clomiphene is essentially luteotrophic and that it has very little, if any, FSH activity. This theory would explain why practically all patients who ovulated after clomiphene therapy had had some prior evidence of estrogenic activity, and why no patient among those who responded had had an atrophic endometrium, or virtual absence of cervical mucus, or very poor vaginal smears. Nor can estrogen be administered to overcome the absence of developed follicles, since clomiphene seems to function in the presence of endogenous estrogen only.

The following represents the author's opinion of clomiphene therapy: (1) It is effective only in the presence of some degree of FSH, as evidenced by at least a slowly developing follicle. (2) It can cause maintenance of the corpus luteum beyond the usual 14-day luteal phase by virtue of its LH effect. (3) It can potentiate the activity of exogenous chorionic gonadotrophin or can substitute for it in some therapeutic situations.
Some laboratory findings suggest that clomiphene can produce suppression of spermatogenesis. If this were the case, one might argue that androgens inhibit spermatogenesis and androgen secretion is stimulated by LH, thus, supporting the argument suggesting LH activity for clomiphene. This point has been emphasized because opinions are divided as to whether clomiphene has any FSH activity or whether it is solely an LH compound.

The following program is suggested for the use of clomiphene in cases of ovulation: (1) Wait until the patient shows evidence of a fairly well-developed follicle. (2) Use short-term administration only and watch the patient carefully. (3) Employ very low dosages as a precautionary measure, approximately 100'00 mg. daily for 4 or 5 days.

A small series of women who wished to use the rhythm method have been started on clomiphene near mid-cycle in an effort to produce ovulation at a specific time. Whether the rhythm method can be made more effective in this way is questionable because other variables, such as, sperm viability and fertilizability of the egg, may be more important.

HMG therapy

As mentioned previously, a substantial number of patients fail to respond to clomiphene presumably because it does not provide any FSH activity. One patient who failed to respond to clomiphene and who had had repeated atrophic endometria on biopsy was given human FSH, a preparation first clinically used by Gemzell in Sweden(4) in increasing doses up to 7 mg. a day. In a relatively short time, she began to show substantial evidence of follicular development. Recognizing that FSH has to be overlapped with LH, some HCG (Follutein) was added. The basal body temperature began to show an ovulatory pattern and the woman became pregnant. Unfortunately, she had a missed abortion in about three months. Since that time she has been placed on HMG (derived from human menopausal urine) and has not as vet become pregnant, although she has again apparently ovulated. Fortunately a number of others have ovulated on HMG (human menopausal gonadotrophin) and have become pregnant as well.

It appears that human FSH is an excellent pituitary preparation but because the supply will undoubtedly be limited for a long period of time, HMG, another FSH-type preparation will have to be used instead. The major source of supply of HMG at the present time is a pharmaceutical company in Italy, where the FSH fraction is extracted and purified from large amounts of urine collected from post-menopausal nuns.
Of 116 patients treated with HMG (some of whom were "oligo-ovulators"), 70 showed evidence of moderate to marked follicular stimulation, 38 showed slight stimulation, and 8 showed no stimulation. Indirect evidence of ovulation was found in 88 patients. The dosages were one to three vials of HMG for periods of four to eight days followed by MRL-41 or by HCG (human chorionic gonadotrophin).

In one case of HMG therapy, the patient ovulated within a few days following the subsequent administration of clomiphene and became pregnant in the same cycle. She subsequently developed a rather involved syndrome starting with abdominal distention and ascites. The patient was hospitalized, subsequently required surgery, and about 6,000 cc. of fluid was aspirated from the abdomen. The ovaries were grossly enlarged, and the presence of multiple corpora lutea indicated that there had been multiple ovulations. With HMG, as with any of the FSH preparations, and also clomiphene, there is a tendency to multiple ovulation resulting in multiple pregnancies.

This type of response occurred in several HMG-treated patients. In one such case, Aldactazide A was administered with the result that the ovarian enlargement subsided and ascites was reduced so that in two to three weeks the patient returned to normal. Since then, Aldactazide A has been successfully used in cases of abdominal enlargement and ascites, although no explanation for its action in such cases can be offered.

This type of excessive stimulation is apparently accompanied by a very intensive development of the corpus luteum. For example, the 24-hour pregnanediol very early in the pregnancy of the last patient cited was 38.1 mg., which is extremely high for that stage of pregnancy.

Preliminary impressions of HMG therapy in infertility cases are: (1) It is a potent FSH preparation. (2) It requires supplementary clomiphene or HCG to induce ovulation. (3) It can stimulate rapid enlargement of ovarian cysts. (4) When pregnancy occurs, it may be associated with a syndrome of large cystic ovaries, abdominal distention, and ascites (possibly related to Meig's syndrome), which respond to aldactone and diuretics. (5) Since most of the patients who do become pregnant, develop this new syndrome, the author is considering the possibility that apparently excessive ovarian stimulation is required for pregnancy in some refractive infertility problems, and he is currently investigating this in a double-blind manner among patients who seem to ovulate regularly. (6) HMG is unlikely to be useful in male infertility, largely because in most instances testes have irreversible changes, with atrophic or hyalinized seminiferous tubules.

REFERENCES
1. Tyler, E. T., Olson, H. J., and Gotlib, M. "The induction of ovula tion with an anti-estrogen," International Journal of Fertility, 5:429, Oct. 1960.
2. Seal, S. J. and Tyler, A. "Inhibiting action of a triphenylethanol derivative on the development of eggs of Arbacia punctulata and the fertilizing capacity of sperm," Biological Bulletin, Oct. 1959.
3. Greenblatt, R. B., Barfield, W. E., Jungok, E. C., and Ray, A. W. "Induction of ovulation with MRL-41," Journal of the American Medical Association, 178:101, 1961.
4. Gemzell, C. A. "Induction of ovulation with human pituitary gonadotrophins," Fertility and Sterility, 13:153, 1962.
5. Tyler, E. T. "The use of human menopausal gonadotrophin in anovulatory problems," paper presented at the meeting of the American Society for the Study of Sterility, Bal Harbour, Florida, April 1964.