Infertility: A Review of 291 Infertile Couples Over Eight Years

Vol. 34, No.2, August 1980 Prinred in U.SA.

FERTILITY AND STERILITY Copyright c 1980 The American Fertility Society

INFERTILITY: A REVIEW OF 291 INFERTILE COUPLES OVER EIGHT YEARS

ADRIAN K. THOMAS, M.B.B.S., M.R.C.O.G., F.(AuSTl.C.O.G.* MICHAEL S. FORREST, M.B.B.S., F.R.C.O.G. Endocrine Clinic, Mercy Maternity Hospital, East Melbourne, Australia

Two hundred and ninety-one infertile couples were studied over an 8-year period. Anovulation was the most common cause of infertility, being the causative factor in half of the patients. Ovulation induction with clomiphene or cyclic hormone therapy readily achieved pregnancy in the majority of these patients. The distribution of other etiologic factors was fairly uniform, but treatment was much less successful. Thorough evaluation of both partners is advised both for treatment purposes and as a more accurate guide to the prognosis for conception. Furthermore, even in the presence of oligospermia, ovulation induction may be successful in achieving a pregnancy. Fertil Steril 34:106, 1980

Recent advances in the understanding of the etiology of infertility have enabled better definition of the various factors involved. Modern approaches to investigation and treatment now include laparoscopy, prolactin assays, and ovulation induction with bromocriptine. Because of the shortage of babies for adoption, pressure for successful treatment is continually increasing. It seemed appropriate, therefore, to review the experience of a clinic during this time of changing investigations and treatment. METHODS

We studied 291 consecutive patients who attended the endocrine clinic of the Mercy Maternity Hospital from the time the hospital opened, in 1971, until March 1978. All patients had been followed for at least 1 year after the initial consultation. The clinic is operated as a secondary referral clinic-patients are referred from other Received March 25, 1980; revised May 28, 1980; accepted June 24, 1980. *Reprint requests: Dr. Adrian K. Thomas, Mercy Maternity Hospital, East Melbourne 3002, Australia.

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clinics within the hospital or from private gynecologists. Investigation A full history was obtained from each patient and a thorough physical examination was carried out. The occurrence of ovulation was assessed by measuring the 24-hour excretion of estrogens and pregnanediol in the midluteal phase in regularly cycling patients or weekly in patients with irregular cycles. Patients were classified as anovulatory if the urinary pregnanediol excretion was less than 2 mg/24 hours. 1 When indicated, thyroid function tests and gonadotropin and prolactin assays were undertaken. In patients with secondary amenorrhea, x-rays of the pituitary fossae were obtained. Tubal patency was initially assessed by hysterosalpingography. Laparoscopy with instillation of methylene blue dye was reserved for those patients with either an abnormal hysterosalpingogram (HSG), or no other known cause for infertility, or those who failed to achieve pregnancy after successful ovulation induction.

106

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TABLE 1. Etiologic Factors in 291 Patients Presenting with Infertility Factor

Anovulation Tubal factor Tubal factor and anovulation Male factor Male and female' factors Unexplained Incomplete investigation Total

107

INFERTILITY: REVIEW OF 291 INFERTILE COUPLES OVER 8 YEARS

Primary infertility

Secondary infertility

Total

'k

tigation and treatment of the female partner.

RESULTS

85 14 7

61 5 6

146 19 13

50.2 6.5 4.5

14 24

4 4

18 28

6.2 9.6

11 24

6 26

17 50

5.8 17.2

179

112

291

Male factor was assessed by semen analysis. A normal result was recorded if the semen contained at least 20 million spermlml with at least 60% motile spermatozoa and 60% normal forms. Treatment

Anovulation. Clomiphene citrate was the definitive agent used for ovulation induction. However, most patients were initially given cyclic hormone therapy (incremental doses of estrogen and progestogen mimicking normal ovarian activity2) for two cycles in attempt to reduce the problem of hyperstimulation with clomiphene. If conception did not occur, clomiphene was then given. The regimen used was as follows: 50 mg/day for 5 days commencing on the 5th day of the cycle; the dosage was increased in subsequent cycles to a maximum of 200 mg/day for 5 days. Response to treatment was assessed by 24-hour urinary estrogen and pregnanediol assays on day 21. In patients with amenorrhea, menstruation was induced with norethisterone acetate, 10 mg/day for 5 days. In the event that ovulation was not induced with clomiphene, suitable patients were referred for gonadotropin therapy. Tubal Obstruction. Tubal surgery was offered to those patients in whom it was felt there was a reasonable chance of success. In addition, reconstructive surgery was undertaken in those patients who strongly requested it, irrespective of the likely prognosis. Male Factor. The male partner was reviewed by a urologist if the semen analysis showed abnormalities. Treatment was administered according to the apparent etiologic factor. However, not all attended, and of those who did initially, a considerable number did not return for subsequent consultation or treatment. The presence of a male factor did not necessarily preclude further inves-

The over-all numbers of patients in the various etiologic groups are shown in Table 1. Half of the patients were anovulatory, whereas there were fairly similar numbers in each of the other groups with the exception of those couples incompletely investigated. The latter group of 50 (17.2%) comprised 21 (7.2%) who became pregnant before investigations could be completed and 29 (10%) who did not return for complete evaluation. Table 2 shows the duration of infertility in these etiologic groups. Patients with anovulatory infertility were equally represented in each category. With other factors there was a tendency for the duration of infertility to be longer, either because the majority of cases of anovulation were symptomatic (amenorrhea) and the patients sought earlier treatment or because other causes tended to be asymptomatic and were less likely to undergo spontaneous resolution. The relative proportions of the etiologic groups do not reflect their incidence in the community, since many patients were referred specifically for investigation and treatment of anovulation. The anovulatory group is therefore abnormally large; conversely, the group with oligospermia is probably smaller than expected because many oligospermic men would have been referred directly to a urologist, without their wives' registering at our clinic. In this respect this report is similar to that ofCox. 3 Anovulation. The etiologic factors found in the 146 patients with anovulation are shown in Table 3. Because the prolactin assay was available only late in the series, this investigation was performed in only 42 of the 143 euthyroid patients. However, TABLE 2. Duration of Infertility in 291 Patients Duration

Total

Factor <1 yr

1-2 yr

>2 yr

Anovulation Tubal factor Anovulation and tubal factor Male factor only Male and female factors Unexplained Incomplete investigation

49 3 2

52 9 4

45 7 7

146 19 13

2 3

4 13

12 12

18 28

1 14

2 18

14 18

17 50

Total

74

102

115

291

August 1980

THOMAS AND FORREST

108

TABLE 3. Etiologic Factors in 146 Anovulatory Patients Etiology

No.

Hypothyroidism Premature menopause Post-contraceptive use Hyperprolactinemia No cause found Total

3 4 31 9 99 146

'* 2.1 2.7 21.2 6.2 67.8 100

9 (21%) had elevated levels and, of these, 3 had radiologic evidence of a pituitary tumor; one patient had minimal visual field loss. This incidence of hyperprolactinemia is consistent with the reports of others. 4 Over-all, 32 patients had post-oral contraceptive amenorrhea, including two with hyperprolactinemia and one with amenorrhea following depotmedroxyprogesterone acetate (Provera) injections. Of the 35 conceptions with clomiphene, 29 occurred in the first two ovulatory cycles, and all pregnancies occurred within the first five ovulatory cycles, thus confirming other reports 5 , 6 that the chances of conception with clomiphene diminish substantially after the first few ovulatory cycles. The results of treatment of patients in the anovulatory group are shown in Table 4 and in graphic form for the whole series in Figure 1, using a life-table method of calculation. Calculating results in this way is advantageous because the method takes into consideration those patients who were lost to follow-up or who no longer required treatment, for example, those who became separated from their partners. The method has been fully reported by Lamb and Cruz. 7 Over-all, the majority of anovulatory patients who became pregnant did so within the first 12 months after registration.

The pregnancy rates obtained in this series are slightly lower than those reported by Hull et al. 8 but better than those reported by Lamb9 and similar to those of Cox. 3 Of the patients with a pituitary tumor, only one was treated during the period of observation. Radiotherapy was initially administered, but prolactin levels remained high and the patient was subsequently treated with bromocriptine. Unfortunately, she was unable to tolerate doses large enough to allow ovulation to occur. The outcomes of the pregnancies which occurred in all of the patients are shown in Table 5. The abortion rate in the group in which ovulation was induced with clomiphene is slightly lower than that in the group with spontaneous conceptions, but the numbers are small. It is also lower than the 18.9% over-all figure computed by the manufacturer lO and comparable to the rate reported by Cox. 3 Tubal Factors. Tubal problems alone were seen in 19 patients (6.5%), which is approximately onehalf the incidence reported by Cox. 3 The HSG was abnormal in all patients with the exception of three of the five women with endometriosis, in whom it was reported to be normal. This failure of hysterosalpingography to diagnose endometriosis is consistent with the experience of Moghissi and Sim11 and Duignan et al. 12 and highlights the need for laparoscopy in selected patients, even when the HSG is reported to be normal. Of the 14 patients with non-endometriotic pelvic adhesions, four became pregnant spontaneously, resulting in two live births, a spontaneous abortion, and an ectopic pregnancy, respectively. This last patient underwent tubal reconstruction at the time of laparotomy for the ectopic pregnancy and subsequently achieved an intrauterine pregnancy which resulted in a live birth.

TABLE 4. Results of Therapy in Anovulatory Infertile Patients Yr after registration

Total

Result

Pregnancy Spontaneous Cyclic therapy Clomiphene Gonadotropin Bromocriptine-thyroxine No pregnancy Premature menopause Pituitary tumor Other Total

D-I'.!

j.;...1

1-2

29 17 12 1 2

4 3 18

4

1

4 2 5

2-3

3-4

37 20 35 5 8

1 2

8

4 2 7

13

5

1 1

69

39

28

8

2

4 3 34

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109

INFERTILITY: REVIEW OF 291 INFERTILE COUPLES OVER 8 YEARS

differences in the criteria for patient selection, as well as the small numbers, no strict comparisons can be drawn between the published results. Multiple Female Factors. Thirteen patients (4.5%) had combined factors of anovulation and tubal disease. In one patient the adhesions were the result of previous wedge resection of the ovaries, a complication which has been recognized elsewhere. 14 Ovulation was successfully achieved in allll patients in whom it was attempted. Over-all, only three pregnancies resulted, of which one was ectopic. No pregnancy followed tubal surgery in this group of patients. Male and Combined Factors. There were 46 couples in whom factors were present in the male partner. Three men were impotent and were referred for psychiatric treatment, which was unsuccessful. An abnormal semen anlaysis was the only defect present in 15 of these 46 couples. The incidence of varicocele in the whole group was 20%, which is comparable to the experience of Hendry .15 Treatment of the male consisted of general advice about the frequency and timing of intercourse as well as the value of wearing loose-fitting underpants. Two patients underwent varicocele ligation during the survey period, resulting in a normal semen analysis in one. His partner unfortunately also had damaged fallopian tubes and pregnancy has not occurred. Eight patients were given mesterolone, 100 mg/ day, for at least 3 months. There was an improvement in the semen characteristics of two of these men, but normal values were not attained and no pregnancy has resulted. However, three pregnancies occurred spontaneously in those couples where only male factors were present. Two of these

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oL-----~-------r------~------r_----~ 4 5 2 3 YEARS AFTER REGISTRATION

FIG.!. Cumulative conception rates for 291 infertile couples. The upper graph represents the anovulatory group of patients; the lower graph, the remainder. Vertical bars show the standard error for the proportion pregnant.

Another six patients underwent tubal reconstruction and three achieved pregnancies, all of which resulted in live births. Endometriosis was treated with dihydrogesterone or norethisterone, or both, and two patients also underwent surgery. Only one patient became pregnant. Danazol was not available for treatment of this condition during the period of observation. The over-all pregnancy rate in this group of 47% with a known live birth rate of37% is encouraging and significantly higher than the results of Cox 3 and Newton et al. 13 However, because of possible

TABLE 5. Pregnancy Outcome in 148 Pregnant Patients Pregnancy outcome

Treatment group

Total no. of patients Abortion

Anovulatory Spontaneous conception Cyclic therapy Clomiphene therapy Other Tubal factor Combined female factors Male factor Male and female factors Other factors Total

7 3 3 2a la 2c 3 21

Live birth

26 17 32 13 7 2 3 4 18 122

Stillbirth

Not known

1

3

1 2 2

alncludes one ectopic pregnancy in each group. bOne patient achieved an intrauterine pregnancy following an ectopic pregnancy. See text. cOne patient aborted twice.

I

5

37 20 35 13 8b 3 3 6 23 148

110

August 1980

THOMAS AND FORREST

pregnancies occurred in the group with severe oligospermia. Three pregnancies occurred after ovulation induction in couples with defects in both partners. Such occurrences highlight the difficulty in establishing the criteria of a normal semen analysis and further demonstrate the concept, as emphasized by Smith et aI., 16 of considering fertility as a function of the couple rather than of two individuals. Other Factors. No impediment to fertility was found in 6% of patients, an incidence lower than the 17.6% reported by Cox3 and the 27% reported by Newton et al. 13 No specific approach to treatment was adopted in this group, but some patients were given clomiphene, bromocriptine, or human chorionic gonadotropin if, on hormone tracking, it was thought that an element of defective ovulation was present. Three pregnancies occurred in this grou}r-two of these in the 4th year after registration. The low fertility rate in these patients is in keeping with a report of a larger group of such patients. 17 Seven per cent of patients became pregnant before investigations were complete. Probably many of these had resumed ovulating just prior to the initial consultation. Another 10% voluntarily declined or did not return for further consultations. A few of these probably have moved from the area or have become pregnant without informing us, but it remains unclear why the majority did not pursue the investigations. Five per cent of patients in one clinic in Sheffield similarly failed to attend. 6

Acknowledgments. We wish to thank Professor N. A. Beischer for his helpful comments; Miss Mary Sheedy, Medical Records Librarian, Mercy Maternity Hospital, and her staff for assistance in retrieval ofthe hospital records; and Mr. Gerard Joyce, Urologist to the Endocrine Clinic for access to his patients' records. Mrs. J. Walstab provided assistance with statistical analysis.

DISCUSSION

REFERENCES

Despite the bias referred to earlier in the selection of patients, anovulation remains the most common cause of infertility. It is also the most easily treated condition and the results oftherapy are encouraging. However, successful treatment of a large proportion of anovulatory patients leaves a group of infertile couples with varying etiologic factors which may be very resistant to treatment. Certainly in our series the conception rate is much lower in the nonovulatory groups than in the ovulatory group. It seems likely that the proportion of couples with multiple infertility factors will increase as a result of the increased incidence of pelvic inflammatory disease associated with sexual promiscuity, abortion complications, and use of intrauterine contraceptive devices. In the male, the current fashion for wearing tight-fitting nylon under-

pants may increase the incidence of oligospermia. Because of this expected increase in multiple etiologic factors it seemed more informative to classify the patients as far as possible into groups with various abnormalities. By doing so, accurate data can be obtained on the natural history of the various conditions and used as a guide to prognosis. Our results show the value offully investigating both partners, as defects are often present in both. When the female partner is anovulatory, ovulation induction is indicated even if the husband's semen analysis is abnormal, as pregnancy may be achieved. If the impaired semen analysis is a result of a varicocele, then treatment of this condition should theoretically improve the chances of conception even further. Those couples with no demonstrable barrier to fertility remain a persistent problem in infertility practice. Almost certainly multiple factors are operative, for example, defective ovulation and immunologic causes, but their proper evaluation is not practicable at this stage except on a research basis, and treatment must remain fairly empirical.

1. Pepperell RJ, Brown JB, Evans JH, Rennie GD, Burger

2.

3. 4.

5. 6. 7. 8.

HG: The investigation of ovarian function by measurement of urinary oestrogen and pregnanediol excretion. Br J Obstet Gynaecol 82:321, 1975 Evans JH, Taft HP, Brown JB, Adey FD, Johnstone JW: The induction of ovulation by cyclical hormone therapy. J Obstet Gynaecol Br Commonw 74:367, 1967 Cox LW: Infertility-a comprehensive programme. Br J Obstet Gynaecol 82:2, 1975 Jacobs HS, Franks S: Diagnosis and treatment ofhyperprolactinaemic amenorrhoea. In Proceedings of a Symposium on Pharmacological and Clinical Aspects of Bromocryptine, Edited by RTS Bayliss, P Turner, WP Maclay. Kent, MCS Consultants, 1976, p 63 Garcia J, Jones GS, Wentz AC: The use of clomiphene citrate. Fertil Steril 28:707, 1977 Thomas AK, Cooke In: Unpublished observations Lamb EJ, Cruz AL: Data collection and analysis in an infertility practice. Fertil Steril 23:310, 1972 Hull MGR, Savage PE, Jacobs HS: Investigation and treatment of amenorrhoea resulting in normal fertility. Br Med J 1:1257, 1979

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INFERTIUTY: REVIEW OF 291 INFERTILE COUPLES OVER 8 YEARS

9. Lamb EJ: Prognosis for the infertile couple. Fertil Steril 23:320, 1972 10. Merrell Laboratories: Product Information, 1972. Cited in Adashi EY, Rock JA, Sapp KC, Martin EJ, Wentz AC, Jones GS: Gestational outcome of clomiphene-related conceptions. Fertil Steril 31:620, 1979 11. Moghissi KS, Sim GS: Correlation between hysterosalpingography and pelvic endoscopy for the evaluation of the tubal factor. Fertil Steril 26:1178, 1975 12. Duignan NM, Jordan JA, Coughlan BM, Logan-Edwards RL: One thousand consecutive cases oflaparoscopy. J Obstet Gynaecol Br Commonw 79:1016, 1972

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13. Newton J, Craig S, Joyce D: The changing pattern of a comprehensive infertility clinic. J Biosoc Sci 6:477, 1974 14. Buttram VC, Vasquez C: Post-ovarian wedge resection adhesive disease. Fertil Steril 26:874, 1975 15. Hendry WF: Male subfertility. In Recent Advances in Urology, Edited by WF Hendry. Edinburgh, Churchill Livingstone, 1976, p 232 16. Smith KD, Rodriguez-Rigau L, Steinberger E: Relation between indices of semen analysis and pregnancy rate in infertile couples. Fertil Steril 28:1314, 1977 17. Lenton EA, Weston GA, Cooke ID: Long-term follow-up of the apparently normal couple with a complaint of infertility. Fertil Steril 28:913, 1977