W. Paul Dmowski

Endocrine properties and clinical application of danazol.

Danazol, a heterocyclic steroid related chemically to 17 alpha-ethinyltestosterone (ethisterone), is currently approved by the FDA for treatment of endometriosis only. However, other clinical applications of the drug may be found for both endocrine and nonendocrine disorders. Hence, the literature of danazol is reviewed. Included are discussions of the chemical structure and biological properties of danazol, which has a basic cyclopentenophenanthrene configuration characteristic of all steroids, and exerts its effects at a subcellular level. Its metabolism and excretion have been studied in animals extensively and in humans via tritiated danazol administration. The drug is well-absorbed from the gastrointestinal system and is rapidly metabolized. Over 60 metaboites have been associated with the metabolic endproduct of tritiated danazol, but only 6 are recognized as metabolites of the drug. Its antigonadotropic effect receives the most attention in the review. In experimental animals various doses of danazol have suppressed gonadal weight (rats), suppressed pituitary gonadotropins (rats and humans), suppressed gonadotropin-releasing hormones (rats and humans), suppressed fertility (rats and rhesus monkeys), and suppressed gonadal steroidogenesis (rats and hamsters). Other biological properties of danazol, besides its primary one of suppression of gonadotropic effect, are related to its androgenicity. Various conceivable clinical applications of danazol are discussed, and its use in therapy of endometriosis is outlined and discussed in detail.

The Luteinized Unruptured Follicle Syndrome and Endometriosis

The identity of luteal structures was evaluated laparoscopically in 199 women. All had evidence of ovulation as judged by dated endometrial biopsies and/or elevated levels of plasma progesterone or urinary pregnanediol. Luteal structures were identified in 159 cases. The stigma was present in 32%, absent in 38%, and questionable in 30% of the latter. No significant differences in the distribution of these findings were observed between patients with endometriosis and patients with male or tubal causes of infertility. However, in patients with clinically diagnosed ovulatory dysfunction, stigmata were observed significantly less frequently. The frequency of stigmata was not related to the varying severity of endometriosis. The earliest time in the menstrual cycle when the stigma was identified was on the day of the basal body temperature (BBT) dip prior to its rise and when the endometrium was late-proliferative. The latest was 11 days after the BBT dip and on day 26 according to endometrial histology. Uncertainty as to the presence of the stigma was frequent. The stigma was present in 33% of women with endometriosis. In some, a corpus luteum with the stigma and endometriosis were present on the same ovary. The hypothesis postulated by some investigators that the luteinized unruptured follicle (LUF) syndrome may be the cause of infertility in women with endometriosis does not appear to be accurate. However, endocrine factors probably play a role in the origin of LUF.

Use of Albumin Gradients for X and Y Sperm Separation and Clinical Experience with Male Sex Preselection

Semen samples obtained from 18 normal males and 37 husbands requesting male child preselection were separated on concentration gradients of human serum albumin. Separated semen obtained from the husbands was then used for artificial homologous insemination (AIH). A significant increase in the sperm motility, progressive drive, and percentage of Y-bearing sperm along with a decrease in the total sperm count and percentage of abnormal forms were observed in separated specimens. Fathers of three or more female children had a slightly smaller but statistically significant percentage of Y-bearing sperm in their semen samples than did normal males. Ten conceptions were achieved with separated semen. Seven pregnancies terminated in normal deliveries of five male and two female infants, one ended in a spontaneous abortion of a male fetus, and two patients are still expecting. The ratio of male to female conceptions in this small study parallels the ratio of Y to X sperm in the final specimen used for AIH.

Artificial Insemination Homologous with Oligospermic Semen Separated on Albumin Columns

Semen samples obtained from 27 infertile men were separated on human serum albumin (HSA) columns prior to artificial homologous insemination (AIH). The columns contained either a single 7.5% HSA layer or two 17.5% and 7.5% HSA layers. Separated specimens were free of seminal debris, had significantly improved motility and progressive drive, and had a decreased percentage of abnormal forms. The total sperm count was also significantly decreased after separation, especially with the two-layer technique. No conceptions occurred in 21 couples when two-layer separation was used, but four pregnancies in 12 couples resulted from AIH with semen separated on the single-layer column. The mean total count of motile sperm obtained for AIH was 5 million with the two-layer and 31 million with the one-layer technique.

Conception following insemination with a freeze-preserved retrograde ejaculate.

Retrograde ejaculation, an infrequent cause of male infertility, may be the sequela of prostate or bladder neck surgery or the result of interruption in the sympathetic innervation to the bladder neck. The diagnosis is established by history and examination of the urine. In infertile couples artificial insemination homologous (AIH) using retrograde ejaculate recovered from the bladder has been successfully accomplished, but conception has occurred only in isolated cases. A literature review of the subject is presented. The technique of semen recovery from the bladder is time-consuming and uncomfortable to the patient, while the quality of the semen recovered is variable and the risk of iatrogenic urinary tract infection is increased. To avoid the above problems, and to have sperm available for AIH at the time of induced ovulation in an anovulatory wife, we were able to freeze-preserve ejaculate recovered from the bladder for future use. A case of conception following AIH with freeze-preserved retrograde ejaculate is presented.

PREMATURE LABOR TREATMENT WITH RITODRINE IN MULTIPLE PREGNANCY WITH THREE OR MORE FETUSES

Abstract. Modern treatment for anovulatory infertility increases the incidence of multiple pregnancies with three or more fetuses and predisposes to prematurity with high perinatal mortality and morbidity. Premature labor was successfully treated in four multifetal pregnancies with ritodrine hydrochloride, a beta‐mimetic drug relaxing the uterus. Another patient misdiagnosed as false labor was not treated and lost three out of four premature babies. Beta‐mimetic treatment is indicated in multiple pregnancies even in false labor, or when painless progress in cervical dilatation is observed, to avoid asymptomatic progression into true labor. In contrast to singleton pregnancies, advanced labor with more than four centimeters cervical dilatation should not preclude good chances for successful treatment. Persistence in treatment and repeated use of the most effective intravenous route combined with oral ritodrine administration is needed because of marked tendency to recurrences of premature labor. Progressive increase in the dose of oral ritodrine may be indicated by decrease in therapeutic response. Maternal tachycardia should be considered as an index of patient responsiveness to the beta‐mimetic treatment. The therapy is most successful when the patient is hospitalized from the first episode of treatment until at least the 37th week of pregnancy. This is probably less expensive than prolonged hospitalization of several prematures in an intensive care nursery.

Effect of intrauterine estriol on reproductive function in the rabbit.

The effect of intrauterine estriol on spontaneous ovulation, ovum fertilization, blastocyst development, and blastocyst implantation in rabbits has been investigated. Estriolreleasing intrauterine capsules constructed of biocompatible polymer were implanted in one uterine horn of adult New Zealand White female rabbits, while placebo-containing capsules were implanted into the contralateral horn. The animals were artificially inseminated and ovulated or mated to fertile bucks. The does were killed and their reproductive tracts were examined 54 hours, 6 days, and 10 days after ovulation-inducing injection or after coitus. The results indicate that intrauterine estriol released at a steady state rate of 1.25 mug/day effectively inhibits blastocyst development and implantation. This contraceptive effect was clearly local, since implantations in the contralateral,placebo-bearing horn were not inhibited. Furthermore, the same dose of estriol, when released systemically from a subcutaneously placed capsule, had no effect on implantation. Intrauterine estriol appeared also to have no effect on spontaneous ovulation or ovum fertilization.

Effect of oral estriol on cervical secretions and on ovulatory response in infertile women.

Estriol in oral doses of 0.25, 0.5, and 1.0mg was administered for 10 days prior to ovulation to six infertile women. All patients kept basal body temperature records and all had frequent examinations of the cervical mucus, the latter recorded as the modified cervical score. Plasma levels of follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, and estriol were determined serially using specific radioimmunoassay techniques in one control cycle and in the three subsequent cycles of treatment. Ten other patients with infertility due to cervical factors were also treated with 0.25mg of estriol. Improvement of the cervical score was consistent and statistically significant during treatment with 0.25mg of estriol, while higher doses of this estrogen had less consistent and statistically not significant effect. The day of the plasma estradiol peak and gonadotropin surge was not changed by 0.25mg of estriol. However, a delay of2 to 9 days in the plasma estradiol and gonadotropin rise was observed in three of six patients receiving 0.5 and 1.0mg of estriol. Three conceptions occurred during treatment. It is concluded that the administration of estriol in a dose of0.25mg/day during the follicular phase of the cycle may be beneficial to infertile patients with a cervical factor. An improved cervical score results from a synergistic effect between endogenous estrogens and exogenous estriol. However, higher doses of estriol may postpone the endogenous estradiol surge and ovulation until after completion of treatment. Thus, no additive effect of endogenous estradiol and exogenous estriol on the cervical mucus is observed.