Karow, W. G., & Payne, S. A. (1968). Pregnancy after clomiphene citrate treatment. Fertility and Sterility, 19(3), 351-362. https://doi.org/10.1016/s0015-0282(16)36663-8
Karow WG, Payne SA. Pregnancy after clomiphene citrate treatment. Fertil Steril. 1968;19(3):351-362. doi:10.1016/s0015-0282(16)36663-8
Karow, William G., and Sheldon A. Payne. "Pregnancy after clomiphene citrate treatment." Fertility and Sterility, vol. 19, no. 3, 1968, pp. 351-362.
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Clomiphene Treatment Was Followed by Pregnancy in 163 of 410 Women
About 4 out of 10 treated women conceived within 6 months of the last dose of clomiphene citrate. The 1968 case series described 410 infertile women with impaired ovarian function at a private Los Angeles clinic. The report describes pregnancy outcomes, side effects, ovulation timing after the last dose, and sperm quality.
Key Findings
Of 410 infertile women treated from May 1962 through September 1966, 163 (39.8%) conceived, producing 180 pregnancies during treatment or within 6 months of the last dose.
Of 140 pregnancies with known outcome, 90 reached term, 19 ended prematurely, 4 ended at 20 to 28 weeks, and 27 ended before 20 weeks, including 2 ectopic pregnancies.
The 140 pregnancies, 12 of them twin pregnancies, produced 124 infants, and 116 survived. Another 39 pregnancies were undelivered and 1 was lost to follow-up.
The 180 pregnancies included 96 with moderately impaired and 29 with poor sperm quality, against 55 with normal quality. The authors judged this out of proportion to expectation.
In 125 women who took clomiphene during the conception cycle, ovulation fell 4 to 17 days after the last day of therapy; 81.6% fell between days 5 and 10.
Interpretation
This is a case series from one private Los Angeles clinic, with no comparison group. Each woman had a full infertility and endocrine evaluation, and a biopsy showed impaired ovarian function as a major or contributing factor in every case. Outcomes are known for 140 of the 180 pregnancies, as 39 were undelivered and 1 was lost to follow-up. The authors judged complication rates similar to those of other infertile women. They found first-cycle abortion and twin rates not significantly different from other cycles.
RRM Context
Restorative reproductive medicine begins by evaluating both partners to find why conception is not happening. The series follows that order: every woman had a full workup, and sperm quality was recorded for male partners, with some impairment in 71% of the couples. Ovulation after the drug varied widely, from 4 to 17 days after the last day of therapy. Cycle charting follows the signs of each woman's own cycle.
Our editorial summary of this paper, not the article's abstract.
Abstract
For years the gynecological endocrinologist has been seeking an effective gonadotrophin for the treatment of ovarian dysfunction and anovulation in the human. 7 Animal preparations have been self-limiting because of allergic reactions, antihormone formation, failure to obtain a uniform response from a standard dose, and the absence of data on animal specificity. A breakthrough occurred in 1958 when Gemzell et al. reported a human pituitary gonadotropin which induced follicular growth and estrogen production in the ovaries of amenorrheic women. The human source does not permit widespread application of this material. A few years later, Pergonal (HMG ),* a human menopausal urine gonadotropin which had similar effects,16 was developed; but standardization of HMG has been difficult and the extraction process complicated and expensive. A most important contribution was made in 1959 by Tyler et al., who were able to induce ovulation in 6 patients with severe anovulatory problems, and in 1960 by Kistner and Smith, who successfully induced ovulation in 4 patients with the Stein-Leventhal syndrome, by using the estrogen antagonist MER 25.t Related compounds were further investigated and clomiphene citrate (Clomidt) proved more effective and had fewer side effects. 5, 12 The exact mechanism of action of the drug is stilI in doubt. It is postulated that clomiphene acts either directly on the hypothalamic-pituitary axis, causing an increase in gonadotropin output,9, 12, 17 or sensitizes the ovary to respond more readily to endogenous gonadotropins. 6 Smith and Kistner believe that Clomid directly influences the enzyme systems involved in ovarian steroidogenesis, or merely acts as a potentiator of gonadotropins. Pildes believes that there is a change in the synthesis of estrogen in both the adrenals and ovaries at the pre-estradiol phase of steroid synthesis. Dickey et al. postulate a direct anti-estrogen effect in the system involved in estrogen metabolism, with subsequent stimulation of the hypothalamic-pituitary axis due to a fall in estrogen levels. Probably more than one mechanism of action is responsible for the response to the drug. We first used clomiphene in the treatment of infertile patients with impaired ovarian function in May 1962. Because of the frequent side effects such as large ovarian cysts, reported by the early investigators, its use was limited to women with major endocrine defects and in cases where all other treatments had failed. With more experience and smaller dosages, 50-200 mg. daily for a short period of time, 3-5 days of each cycle, the drug was effective and most of the side effects were eliminated.14 With a program of at least monthly checkups, the drug proved safe and we have extended its use to infertile patients with only minor problems of ovarian dysfunction. All patients, prior to treatment, have a thorough infertility and endocrine evaluation. The patient who is a proper candidate for this drug should be one with a moderately intact pituitary-ovarian axis and norm~or low total urinary gonadotropin levels, although we have had several patients with mildly elevated total gonadotropin who have responded. The patient should have a fair endogenous estrogen production. Thyroid function is usually normal or mildly subnormal. The 17-ketosteroid concentration is usually normal, although 32.5% of our patients who conceived did show levels of 13.0 mg. 24 hr. or more. Several of these decreased to normal levels after treatment with clomiphene; Pildes has reported a similar finding. Of our patients who conceived, 35.5% showed a diabetic or a prediabetic glucose tolerance curve on initial evaluation. Pituitary tumors should be ruled out. Patients with ovarian damage due to chronic infection are not likely to respond. Since clomiphene citrate is detoxified in the liver, one should be hesitant to prescribe the drug to a patient with chronic liver disease. Visualization of the ovaries by culpotomy with ovarian biopsy or culdos-copy is helpful in establishing the diagnosis, especially in patients who fail to respond.
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