Clomiphene-Regulated Ovulation for Donor Artificial Insemination*

FERTILITY AND STERILITY Copyright © 1976 The American Fertility Society

Vol. 27, No.4, April 1976 Printed in U.SA.

CLOMIPHENE-REGULATED OVULATION FOR DONOR ARTIFICIAL INSEMINATION* LEONARD J. KLAY, M.D.t

Department of Obstetrics and Gynecology, Sonoma County Community Hospital, Santa Rosa, California 95401

Seventeen couples with male-caused infertility requested donor artificial insemination between January 1,1973, and December 31, 1974. All of the women were evaluated prior to the inseminations and were found to be ovulatory. They were treated with clomiphene citrate, 50 mg/day for 5 days beginning on day 4,5, or 6 of a menstrual cycle, and scheduled for two inseminations on the 5th and 7th days after completion ofthe clomiphene regimen. Fresh semen placed in cervical cups was used for the inseminations. The procedure was repeated in the following months until conception occurred. Of the 17 patients, 16 conceived during a total of29 treatment cycles. Of those 16 patients, 59% conceived during the first cycle, 23% during the second cycle, and 12% during the fourth cycle. The only patient who failed to conceive abandoned the procedure after two failures. Seventeen pregnancies occurred. Two ended in spontaneous abortion at 10 weeks, confirmed by pathologic examination of the tissue. Thirteen patients delivered apparently normal infants at term (eleven males and six females). Two patients delivered fraternal twins. The pregnancy rate of 94% during a mean of 1.7 treatment cycles is better than that reported previously. The reasons for this success are related to a number offactors, including the use offresh semen, careful insemination techniques, and perhaps the use of clomiphene for ovulation induction.

Improved and more widely disseminated family planning services and the increasing numbers of legal abortions in the United States have brought the birth rate to an all-time low and virtually eliminated children available for adoption. As a result, more couples are requesting donor artificial insemination (AID) when a male factor is identified as the cause of infertility. The most difficult technical aspects of Received April 10, 1975. *Presented at the Thirty-First Annual Meeting of The American Fertility Society, April 3 to 5, 1975, Los Angeles, Calif. tReprint requests: Leonard J. Klay, M.D., 990 Sonoma Avenue, Suite 15, Santa Rosa, Calif. 95405.

AID are the reliable and predictable determination of ovulation and the timing of the inseminations. Clomiphene has been used successfully and safely to induce ovulation in hundreds of anovulatory and infertile women, resulting in normal offspring. Although it is not generally recommended for use in ovulatory women, clomiphene was used in this selected group of patients to produce predictable and regulated ovulation, to allow time to schedule the inseminations when office personnel and donors were readily available, to improve the pregnancy rate, and to decrease the emotional and financial burdens of repeated AID failures.

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MATERIALS AND METHODS

Between January 1, 1973, and December 31, 1974, 17 couples with malecaused infertility from my practice and referred by other physicians in the area requested and were found suitable for AID. The husband and the wife were interviewed together and encouraged to discuss their feelings about AID. The techniques of insemination, the selection of donors, the use of clomiphene to induce ovulation, and the reported pregnancy rates of AID were explained and discussed with the couples. A confidential AID consent form was given to them and they were asked to return this form at the time of their next visit. All men who were azoospermic or oligospermic (less than 10 million/m!) had had or were referred for urologic evaluation prior to insemination and were believed to have uncorrectable problems. The men who had had vasectomies were referred for evaluation and counseling concerning vasovasostomy. One man had undergone an unsuccessful vasovasostomy and the others decided against the surgery. All of the women provided a complete gynecologic history including age, parity, and menstrual history, and a history of previous pelvic infections, other illnesses, and surgery. Pelvic examinations were made and Papanicolaou smears were obtained. Each woman was instructed to keep a basal body temperature record, and at least one full cycle was reviewed before the first insemination was scheduled. After the initial evaluations were completed, the husband and wife were seen again before the first inseminations were scheduled. The patient was instructed to call on the 1st day of the next menstrual cycle. At that time it was determined what day the patient would begin a 5-day course of clomiphene (50 mg/day) and what days the inseminations would be

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performed. Two inseminations were scheduled 5 and 7 days after completion of the clomiphene regimen, and the 1st day of treatment was adjusted to begin on the 4th, 5th, or 6th day of the menstrual cycle so that the insemination days were weekdays, when office personnel and donors were available. After the inseminations were scheduled, the donors were contacted. The donors were selected from the medical student, intern, and resident population of the area and matched as closely as possible to the ethnic and physical characteristics of the husband. Donor semen was collected, by masturbation, in sterile sputum containers; picked up by me directly from the donor; and taken to the office, where the inseminations were performed within 1 hour of collection. The same donor was used for the two inseminations performed during each treatment cycle. A stemmed Milex cervical cup was used for the two inseminations. The patient was placed in the dorsolithotomy position and a Graves vaginal speculum was inserted. The entire semen specimen was placed in the cup and the cup was applied directly to the cervix. The patient remained in this position for half an hour and then was allowed to go home. She was instructed to remove the cup in 4 hours and to return for the second scheduled insemination in 48 hours. The patients continued to record their basal body temperatures (see example in Fig. 1) and they were instructed to call for a new appointment and examination on the 1st day of the next menstrual period. If menses began and there was no evidence of ovarian cyst formation, clomiphene was again prescribed for a 5-day course and repeat inseminations were scheduled. If the basal temperature remained elevated for 3 weeks, the patient was presumed to be pregnant and the pregnancy was confirmed by examination and Gravindex.

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FIG. 1. Basal body temperature chart of a clomiphene-treated woman who conceived by AID. RESULTS

Between January 1, 1973, and December 31, 1974, 17 couples requested and underwent AID with clomiphene-regulated ovulation (Table 1). All of the women had ovulatory cycles with biphasic

basal body temperature records and normal pelvic examinations prior to the inseminations. The reasons for infertility are summarized in Table 2. Six men were azoospermic and three men had severe oligospermia which failed to improve with

TABLE 1. Results of AID with Clomiphene-Regulated Ovulation No.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Reason for infertility

Azoospermia Vasectomy Azoospermia Vasectomy Azoospermia Azoospermia Vasectomy Vasectomy; failed vasovasostomy Oligospermia (5 million/ml) Vasectomy Oligospermia (10 million/ml) Oligospermia Testicular tumor; orchiectomy, irradiaton Azoospermia; diabetes mellitus Azoospermia Vasectomy Vasectomy

aD&C, Dilatation and curettage.

Treatment cycle of pregnancy

1 1 1 1 1 1 1 1 2 2 1 None 4 4 2 2 1 1

Delivery date

Outcome"

5/8175 5/12175

Spontaneous abortion, 10 wk; D&C Female, 7 lb 8 oz Male, 7 lb 8 oz Female, 7 lb 4 oz Female, 7 lb 2 oz Male, 7 lb 7 oz Male, 7 lb 11 oz Male, 6 lb 13 oz Spontaneous abortion, 10 wk; D&C Male, 7 lb 12 oz Twins, 35 wk; females, 5 lb, 4 lb 4 oz Abandoned procedure after two failures Male, 9 lb Male, 7 lb 13 oz

717175 7/5175 7/13175 8/30175

Twins; male, 7 lb 8lh oz; female, 6 lb Male, 7 lb 7 oz Male, 8 lb 4 oz Male, 6 lb 7 oz

7/23173 8/14174 2/21174 6/9174 6/22174 11/14174

11/20174 11/30174 11/30174 117175 2/10175

TABLE 2. Reasons for Infertility Reason for infertility

No. of men

Azoospermia Severe oligospermia (less than 10 millionlml) Previous vasectomy Testicular tumor (orchiectomy, irradiation) Total

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KLAY

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6 3 7 1 17

treatment. One man had had a testicular teratoma 3 years previously and was sterile because of a bilateral orchiectomy and radiation therapy. Seven men had had vasectomies 4 to 10 years previously. One had undergone an unsuccessful vasovasostomy and the other six men decided against surgery. Sixteen of the seventeen patients became pregnant during a total of 29 treatment cycles, with a calculated pregnancy rate of 94% during an average of 1.7 treatment cycles (Table 3). Two patients who conceived had spontaneous abortions at 10 weeks. One returned for a second insemination and again conceived during the first treatment cycle; she delivered a normal infant at term. The one patient in this series who failed to conceive abandoned the procedure for financial reasons after two failures. There were 17 pregnancies in this series. Eleven (59%) occurred during the first treatment cycle, four (23%) during the second treatment cycle, and two (12%) during the fourth cycle. Fifteen patients delivered apparently normal infants (eleven males and six females) (Table 4). Two patients delivered fraternal twins. The-

first patient delivered twin female infants weighing 5 pounds and 4 pounds, 4 ounces at 35 weeks' gestation. The second patient delivered a 7-pound 81hounce male and a 6-pound female at full term. There were two spontaneous abortions at 10 weeks' gestation. Pregnancy was confirmed by histologic examination of tissue obtained by dilatation and curettage. TABLE 4. Outcome of Pregnancy Outcome

No. of patients

15

Delivered

Spontaneous abortion, 10 wk; confirmed pregnant by D&C a Total

Remarks

Two sets of twins: females 5 lb, 4 lb 4 oz; male 7 lb 8Y.! OZ, female 6 lb: 6 females, 11 males

2

17

aD&C, Dilatation and curettage. DISCUSSION

Successful AID depends on an accurate determination of ovulation and properly timed and carefully performed insemination techniques. Reported pregnancy rates for AID with fresh semen range from 98% during a mean of 3.04 treatment cycles utilizing a cervical cup for 48 hours,! to 52% during a mean of 3.8 treatment cycles with the semen specimen placed directly into the endocervical canal and posterior vaginal fornix. 2 The average pregnancy rate with fresh semen was approximately 70% during four treatment cycles.1-7 Pregnancy TABLE 3. Treatment Cycle in Which rates with frozen semen were considPregnancy Occurred erably lower. 7- 9 The timing of the in% No. of treatment No. of Treatment Pregnant cycles cycle pregnancies seminations was based on several fac59 11 11 1 tors, including analysis of previous basal 23 8 4 2 body temperature records, daily exami12 8 4 2 nation of the cervical mucus near mid0 2 Failureb 0 cycle for ferning and spinnbarkheit, 94 29 Total 17 and daily determination of the karyopyknotic index. Delay in ovulation and a Pregnancy rate, 94% during 1.7 treatment cycles. bOne patient abandoned AID after two failures. subsequent thermal shift have been obu

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CLOMIPHENE·REGULATED OVULATION FOR AID

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served in patients undergoing AIDlO,l1; week, when donors and office personnel therefore, insemination timing based were readily available; and (4) with an solely on analysis of previous basal body accurate determination of ovulation, the temperature records frequently fails. pregnancy rate could be maximized, alDaily examination of cervical mucus for lowing a decrease in the total number ferning, spinnbarkheit, and vaginal cy- of treatment cycles required and thus detology near midcycle is time-consuming, creasing the emotional and financial subjective, and inconvenient for the phy- stress on the patients. sician, and increases the emotional and The occurrence of two fraternal twin financial burden for the patient. Also, gestations in this small group of patients donors are not always immediately avail- suggests that the clomiphene was the able when the optimal time for insemi- successful stimulus for ovulation in these nation occurs. patients. However, as there was no The difficulty in determining ovulation double-blind control group in this study, has led to attempts to induce ovulation it cannot be concluded that clomiphene medically in patients undergoing AID. alone was the only reason for the high Behrman and Sawada8 reported a suc- pregnancy rate. cessful pregnancy following Pergonal and Other factors in the insemination proAPL therapy in a patient with very ir- tocol were probably also important in imregular cycles. Kohane et al. 11 and Fuchs proving the pregnancy rate. Fresh, rathet al. 12 reported successful pregnancies er than frozen, semen was used since following human chorionic gonadotropin higher pregnancy rates have been readministration when daily examination ported with the use of fresh semen. 9 , 11 of cervical mucus showed marked es- A cervical cup and the entire semen specitrogenic activity. Most recently, syn- men were used in order to concentrate thetic luteinizing hormone-releasing the semen at the cervix, rather than hormone has been used to induce ovu- endocervical or vaginal deposition of the lation in patients undergoing AID.13,14 semen, as the highest pregnancy rates However, only four pregnancies oc- occurred with this technique. 1, 14 Two incurred in nineteen patients and only seminations 48 hours apart were used as 60% of the ovulations were sufficiently Torrano and Murphy16 reported that conclose to the administration of the luteini- ception was most likely to occur 2 days zing hormone-releasing hormone to sug- before the rise in basal body temperature. gest cause and efIect.14 The temperature rise following clomiClomiphene has been widely and safely phene administration usually occurs 6 to used to induce ovulation in anovulatory 9 days after completion of a 5-day course; women, and more than 2000 successful therefore, days 5 and 7 seemed optimal pregnancies have been reported, with no for insemination. higher rate of birth defects than that for normally conceived infants.15 ClomiREFERENCES phene was selected for regulated ovulal. Langer G, Lemberg E, Sharf M: Artificial intion in this special group of patients besemination, a study of 156 successful cases. cause (1) it was believed to be a safe Int J FertilI4:232, 1969 and reliable means of inducing ovula2. Raboch J, Tomasek ZD: Therapeutic donor insemination: results. J Reprod Fertil 14:421, tion; (2) ovulation could be predicted well 1967 in advance of the planned inseminations; 3. Murphy DP, Torrano EF: Donor insemination: (3) the beginning of the course of treata study of 112 women. Fertil SterilI7:273, 1966 ment could be modified, allowing in4. Behrman SJ: Artificial insemination. Int J semination days to occur during the Fertil 6:291, 1961

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5. Kleegman SJ: Therapeutic donor insemination. Conn Med 31:705, 1967 6. Hill AM: Experiences with artificial insemination. Aust NZ J Obstet Gynaecol10:112, 1970 7. Steinberger E, Smith KD: Artificial insemination with fresh or frozen semen. JAMA 223: 778, 1973 8. Behrman SJ, Sawada Y: Heterologous and homologous inseminations with human semen frozen and stored in a liquid-nitrogen refrigerator. Fertil Steril17:457, 1966 9. Matheson GW, Carlborg L, Gemzell C: Frozen human semen for artificial insemination. Am J Obstet Gynecol104:495, 1969 10. Murphy DP, Torrano EF: The day of conception: a study of 48 women having two or more conceptions by donor inseminaiton. Fertil Steril 14:410, 1963

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11. Kohane ES, Sharf M, Kuzminsky T: The use of HCG in delayed ovulation during artificial insemination. Fertil Steril 18:593, 1967 12. Fuchs K, Brandes JM, Paldi E: Enhancement of ovulation by Chorigon for successful artificial insemination. Int J Fertil11:211, 1966 13. Nakano R, Mizuno T, Kotsuji F: Triggering of ovulation after infusion of synthetic luteinizing hormone releasing factor (LHRF). Acta Obstet Gynecol Scand 52:269, 1973 14. Taymor ML: The use of luteinizing hormonereleasing hormone in gynecologic endocrinology. Fertil Steril 25:992, 1974 15. Reports on file. Merrell-National Laboratories, Division of Richardson-Merrell Inc, Cincinnati, 0,1972 16. Torrano EF, Murphy DP: Cycle day of conception by insemination, or isolated coitus. Fertil Steril 7:492, 1962