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Norethynodrel with Mestranol in Infertility
Norethynodrel with Mestranol in Infertility W. S. M. ARRATA, M.D., and GEORGE H. ARRONET, M.D.
present themselves to our center with a history of infertility despite the fact that no contraception has been practiced, all the basic diagnostic procedures are performed to rule out organic disease in the genital organs or elsewhere in the reproductive system. These procedures include complete physical examination of both partners, semen analysis, basal body-temperature recordings, tubal insufHation, endometrial biopsy, postcoital tests with evaluation of the cervical changes at ovulation, hysterosalpingogram, serial vaginal cytologic studies, and if necessary, endocrine assays, dilatation and curretage, culdoscopy, and evaluation of the spermatozoal antibodies, in a routinely sequential manner.4 Once an organic cause for the infertility has been eliminated, the patients are then classified in one of the 4 following categories according to their functional ovarian status: 1. Ovulatory Patients in whom ovulation has been occurring regularly at or around midcycle, for at least 6 consecutive menstrual cycles 2. Anovulatory Patients in whom there has been no evidence of normal ovulation for at least 6 consecutive months, regardless of clinical menstrual pattern 3. Subovulatory Patients in whom normal ovulation does not occur in at least 2 of 6 consecutive menstrual cycles These 3 groups are diagnosed by evaluating the monthly basal bodytemperature recordings; at least 2 endometrial biopsies are performed during the 6-month period. Urinary pregnanediol and glucosamine determinations, serial vaginal cytologic studies, and spinnacity are confirmatory. 4. Luteal-phase inadequacy In patients in this category, the condition is diagnosed by evaluating basal body-temperature recordings, endometrial
WHEN A COUPLE
From the Infertility Center, Department of Obstetrics and Gynecology, Royal Victoria Hospital, and McGill University, Montreal, Canada. Presented at the lIth Annual Meeting of the Canadian Society for the Study of Fertility, Vancouver, B. C., Canada, June 17 and 18, 1964. The Enovid used in this stndy was supplied by G. D. Searle & Co. of Canada Ltd., Brampton, Ont., Canada.
430
.. VOL.
16, No.4, 1965
PROGESTOGENS I}.< INFERTILITY ,~
.
431
biopsies, pregnanediol values, and vaginals cells. At least 2 of the 4 test results should be abnormal for luteal-phase inadequacy to be definitely diagnosed. PRESENT STUDY ,.
Many functions and uses have been attributed to norethynodrel with mestranol (Enovid) with varying reports of success. In our center, the drug was given to infertile women with the purpose of achieving a successful rebound~phenomenon in cases of idiopathic infertility with normal ovarian function and in subovulatory and anovulatbry patients; it was also used to treat proven cases of luteal-phase inadequacy.
METHODS AND MATERIAL
Enovid was given to 72 patients; however, 4 patients did not return for treatment, 3 had 1 cycle of treatment or less, and 6 discontinued medication. Ovarian dysgenesis was found in 1 and Stein-Leventhal syndrome in 2; this reduced the number of patients in the study to 56. For the rebound phenomenon, we used 2.5 mg. norethynodrel with 0.1 mg. mestranol, or 5 mg. norethynodrel with 0.075 mg. mestranol, starting on Day 5 of the cycle and continuing for 20 days. The dose was doubled in cases of breakthrough bleeding. The compound was given for a minimum of 3 to a maximum of 9 induced menstrual cycles, with an averages of 4 to 5 cycles. The 36 patients in this group received Enovid for 167 cycles, with an average of 4.6 cycles per patient. In cases of proven luteal-phase inadequacy, the 5-mg. tablet, or the lO-mg. tablet, the latter containing 9.85 mg. norethynodrel with 0.15 mg. mestranol, was given immediately following the temperature rise in the basal bodytemperature recording for a minimum of 10 days, then resumed in the subsequent 4-5 cycles if a pregnancy test proved negative or if bleeding ensued on withdrawal of the drug. It was necessary on occasions to supplement the therapy with estrogens during the first half of the menstrual cycle. If a patient conceived while taking the drug, the therapy was carried on until at least the twelfth week of gestation, to prevent an abortion which might occur on withdrawal of the drug. This group consisted of 20 patients. Luteal-phase inadequacy was suspected when one of the four diagnostic tests had abnormal results, and was confirmed by at least one of the other three.
432
ARRATA & ARRONET
FERTILITY & STERILITY
RESULTS
Of the 56 patients, 24 (42.7%) conceived after therapy, 7 improved in ovulatory or menstrual status, and 25 showed no improvement (Table 1). Most of the failures were among the anovulatory patients with a history of primary infertility. It is interesting to note that 12 of the pregnancies (50%) occurred in the first month after withdrawal of Enovid, and 3 occurred in the second month (Fig. 1). Pregnancies occurring 1 year or more after therapy were not listed as positive results, but considered as late improvement of the original defect. In the group of 36 patients selected for attempted rebound phenomena,
Fig. 1. Incidence of pregnancies after Enovid therapy.
1
2
3
5
4
6
7 - 12
MONTHS AFTER ENOVID THERAPY
TABLE 1. Results of Enovid Therapy in 56 Infertility Patients with Regular and Irregular Menstrual Cycles Ovulatory l'leg.
Menses regulated Ovulation regulated Failures
Sub ovulatory
lrreg.
Re.q.
3 3
4
2 0
[rreg.
1 0 3
Anovulatory Reg.
[rreg.
Total
4
0 3
0 1 12
3 25
3 1
11 1
30 8
1 0
6 3
26 16
PRIMARY INFERTILITY No. of patients Conceptions
3 0
8 3
2 1
3 2
SECONDARY INFERTILITY No. of patients Conceptions
1 1
10 8
2 1
6 3
VOL.
16, No. 4, 1965
PROGESTOGENS IN
433
INFERTILITY
13 patients (36%) conceived (Table 2). Most of these were in the subovulatory group, with 7 pregnancies in 11 patients. The anovulatory patients showed improvement in only 28.6% of cases. There were 75% failures in the ovulatory group, but the statistical significance of these results is questionable because of the small sample. In the group of 20 patients with luteal-phase inadequacy, 11 (55%) conceived (Table 3). There were 6 failures in that group, and 3 patients improved on therapy although no pregnancies ensued. Of the 11 pregnancies resulting after treatment of the luteal-phase inadequacy, 5 (45.4%) ended in live births, 1 (9.2%) was ectopic, and 5 (45.4%) ended in abortions. Perhaps the low salvage rate might be attributed to the effect of the compound on the endometrium (arrest in development of the glandular component), rendering it unfavorable for nidation of the fertilized ovum. COMMENT The Rebound Phenomenon
An increase in the fertility potential has been noticed in many patients after withdrawal of progestogens taken for contraception. This interesting TABLE 2. Rebound after Enovid Therapy Cyrles No. of Ovulation status
Ovulatory Subovulatory Anovulatory TOTAL
patient.~
4 11
21 36
Range per patient
2-4 3-8 3-9 2-9
Total
Pl'egnanrie,.
Ovulation
Faihtre .•
1 7 5 13
2 1 3
3 2 15 20
12 49 106 167
TABLE 3. Results of Envoid Therapy in Luteal-Phase Inade.quacy (LPI) Group Cycles
Test
Basal body temperature Endometrial biopsy Urinary pregnanediol Vaginal smears TOTAL
No. of patients
7 8 2 3 20
Ran.qe per patient
2-6 1-10 2-5 3-8 1-10
Total
24 32 7 16 79
LPI corLPI rected and corrected pregnancy Failures
1 1 1 3
5 5 1
1 2 1 2
11
6
434
ARRATA & ARRONET
FERTILITY
& STERILlTY
phenomenon was first reported by Rock et al.;26, 27 Subsequent studies supported and contradicted their finding. 16 , 18,28,35 Among their diverse gonadal effects, progesterones suppress pituitary function. Vasicka and Richter proved that Enovid does not influence FSH, since recently stimulated follicles are present in abundance, but inhibits the luteinizing hormone, resulting in the arrest of final stages of follicular maturation, and thus preventing ovulation. Whether Enovid prevents adequate release of LH from the pituitary or inhibits its formation by the gland is debatable. If progesterone prevents release of the gonadotropins, these will accumulate during progesterone administration. When the drug is withdrawn, their sudden release may trigger ovulation in anovulatory patients, regulate it in subovulatory cases, or cause multiple ovulation with more than one ovum available during one menstrual cycle. Should the progesterone effect be inhibition of pituitary gonadotropin formation, this period of physiologic rest might be followed later by a betterfunctioning gland. Such an assumption could only be confirmed by qualitative LH bioassays. Although progestins do not supposedly affect the ovary directly, but only through the mediation of the pituitary gland, their action on the endometrium is most probably direct action. Luteal-Phase Inadequacy
The introduction of luteal-phase inadequacy as a cause of infertility has aroused much interest. There have been many reports as to its causes and diagnosis, and many conflicting opinions as to modes of treatment and their results.7, lr" 17, 19,21,22,33,35 We have classified luteal phase inadequacy as physiologic, organic, and functional. Physiologic inadequacy would be due to the postpartum state and menopause. Organic inadequacy would be due to the inability of endometrium to respond adequately to normal hormonal stimuli, because of developmental inadequacy, inflammation, or sclerosis, or due to ovarian insufficiency, in which the deficient hormonal stimulus is unable to elicit an adequate response in a normal endometrium, because of ovarian inflammation, tumors, or other causes of ovarian insufficiency. Functional inadequacy might be due to nutritional insufficiencies, intoxications, systemic diseases, or endocrinopathies such as those produced by psychogenic or neurogenic factors, pituitary insufficiency, hypo- or hyperthyroidism, or adrenal hyperfunction.
VOL.
16, No.4, 1965
PROGESTOGENS IN INFERTILITY
435
Diagnostic Criteria BASAL BODY TEMPERATURE. The presence of luteal-phase inadequacy is suspected if basal body temperature shows (1) a gradual rise at the time of ovulation, (2) a short luteal phase lasting less than 10 days, (3) an unsustained, down-slanting postovulatory phase, and (4) a drop to the preovulatory level for any 2 recordings during the luteal phase. ENDOMETRIAL BIOPSY. Biopsy is performed on or around Day 25 of the menstrual cycle. The specimen is dated and then correlated with ovulation time as determined by the basal body-temperature chart, and with the onset of the next menses. 23 We consider a delay of more than 2 days in endometrial development in relation to ovulation or to the onset of the next menses as a sign of luteal-phase inadequacy. URINARY PREGNANEDIOL. The average values for pregnanediol in our laboratory vary from 2 to 7 mg./24 hr. during a normal luteal phase. 20 Readings of 2 mg. or less per 24 hr. at any time during the progestational phase are good evidence of an inadequate luteal phase. VAGINAL SMEAR. Taking vaginal smears is an adequate method of determining and confirming poor luteal function. One reading is usually unreliable; a good test should include a series of smears taken during the second half of the menstrual cycle, so that the actual sequence of events involving the vaginal cells' desquamation could be properly evaluated. 5
DISCUSSION
A Dutch anatomist, Regner De Graaf, was the first to publish a description of the corpus luteum, in 1672, and the earliest illustration of that organ is seen in his plate of the cow's ovary.10 In 1898, the French histologist Prenant suggested that the corpus luteum is an organ of internal secretion. Two years later, the embryologist Gustav Born conceived the idea that the specific endocrine function of the corpus luteum is to protect the early embryo and facilitate its implantation; in 1903, his former student Fraenkel showed that removal of the corpora lutea of rabbits, early in pr~gnancy, invariably caused the embryos to disappear. I • 8 In 1910, Ancel and Bouin described the secretory changes of the rabbit's endometrium under the influence of the corpus luteum. 8 In 1929, Corner and Allen proved that the hormone progesterone is present in lipoid extracts of the corpus luteum, D and further purified preparations were isolated in 1931 and 1932. After the establishment of the structural formula and the synthesis of pure progesterone in 1934,3 a 20-year period followed that brought controversies
436
ARRATA & ARRONET
FERTILITY & STERILITY
concerning the role of progesterone in the maintenance of pregnancies and abortions. However, in the early 1950's, interest was aroused again by the discovery of compounds similar or related to progesterone/I, 32 and by their gonadal effects, especially inhibition of ovulation through the mediation of the pituitary gland. 6 , 14, 16, ~4-27, 29 Norethynodrel with mestranol (Enovid) was one of the earliest progestogens to be tested in this field. Numerous excellent reports dealing in detail with the chemistry, animal and human pharmacologic activities, and toxicity of norethynodrel are available. I:!, 13, 29-31 CONCLUSIONS
1. Norethynodrel with mestranol (Enovid) was effective in regulating ovulation and consequently improving the pregnancy rate for patients in whom ovulation, although present, was irregular. 2. Enovid was found successful in treating luteal-phase inadequacy. The pregnancy outcome was 55%, although 45.4% of these pregnancies terminated in abortions. 3. Little success was achieved in treating anovulatory patients, most of whom had primary infertility; some beneficial effect was achieved in cases of secondary infertility. 4. Statistical evaluation of results in the normal ovulatory group was not possible because of the size of the sample. Royal Victoria Hospital Montreal 2, Canada
REFERENCES 1. ALLEN, E., and DOISY, E. A. Ovarian hormone: preliminary report on its localization, extraction and partial purification and action in test animals. ]. A. M. A. 81: 819, 1923. 2. ALLEN, W. M., BUTENANDT, A., CORNER, G. W., and SLOTTA, K. H. Nomenclature of corpus luteum hormone. Science 82: 153, 1935. 3. ALLEN, W. M., and WINTERSTEINER, O. Crystalline progestin. Science 80:190, 1934. 4. ARRONET, G. H., and SMITH, N. E. Suggestions for the organization of an infertility center. Fertil. & Steril. 14: 1, 1963. 5. ARRONET, G. H., and TURNBULL, L. Colpocytogram and cornification index; suggested standard for the reading of vaginal smears in the normal menstrual cycle.
Fertil. & Steril. 8:465, 1957. 6. ASTWOOD, E. B., and FEVOLD, H. L. Action of progesterone on gonadotropic activity of pituitary. Am. J. Physiol. 127: 192, 1939. 7. COHEN, M. R, and HANKIN, H. The inadequate luteal phase. 1nternat. J. Fertil. 4: 58, 1959. 8. CORNER, G. W. "A Hormone for Gestation." In The Hormones in Human Reproduction. Princeton, Princeton, N, J., 1942, p. 103.
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PROGESTOGENS IN INFERTILITY
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9. CORNER, G. W., and ALLEN, W. M. Physiology of the corpus luteum. Am. ]. Physiol. 88:326, 1929. 10. DE GRAAF, R. De Mulierum Organis Generationi Inservientibus (Leyden, 1672). Chapter 12, p. 71. Translated by Corner, G. W. "On the Female Testes or Ovaries." In Essays in Biology. Univ. California Press, Berkeley, 1943, p. 121. 11. DJERASSI, C., MIRAMONTES, L., and ROSENKRANZ, G. 19-norprogesterone, a potent progestational hormone. ]. Am. Chem. Soc. 75:440, 1953. 12. DRILL, V. A. Steroids inhibiting ovulation. Jap. ]. Pharmacol. n:88, 1962. 13. EDGREN, R. A. The uterine growth-stimulating activities of 17a-ethynyl-17-hydroxy5 (10) -estren-3-one (norethynodrel) and 17a-ethynyl-19-nortestosterone. Endocrinology 62:689, 1958. 14. EpSTEIN, J. A., KUPPERMAN, H. S., and CUTLER, A. Comparative pharmacological and clinical activity of 19-nor-testosterone and 17 -hydroxy-progesterone derivatives in man. Ann. N. Y. Acad. Sc. 71:560, 1958. 15. Foss, B. A., HORNE, H. W. JR., and HERTIG, A. T. The endometrium and sterility. Fertil. & Steril. 9: 193, 1958. 16. GARCIA, C. R., PINCUS, G., and ROCK, J. Effects of three 19-nor steroids on human ovulation and menstruation. Am.]. oi)st. & Gynec. 75:82, 1958. 17. GILLAM, J. S. Study of the inadequate secretion phase endometrium. Fertil. & Steril. 6: 18, 1955. 18. GOLDZIEHER, J. W., et ai. Fertility following termination of contraception with norethindroen. Am. ]. Obst. & Gynec. 84: 1474, 1962. 19. GRANT, A., McBRIDE, W. G., and MOYES, J. M. Luteal phase defects in sterility. Internat. ]. Fertil. 4:315, 1959. 20. KLOPPER, A. I. Excretion of pregnanediol during the normal menstrual cycle. ]. Obst. & Gynaec. Brit. Emp. 64:504, 1957. 21. MALKANI, P. K. Inadequate secretory endometrium. Internat.]. Fertil. 7:53, 1962. 22. MOSZKOWSKI, E., WOODRUFF, D., and JONES, G. S. The inadequate luteal phase. Am. ]. Obst. & Gynec. 83:363, 1962. 23. NOYES, R. W. Uniformity of secretory endometrium. Obst. & Gynec. 7:221, 1956. 24. PINCUS, G., CHANG, M. C., HAFEZ, E. S. E., and ZARROW, M. X. Effects of certain 19-nor steroids on reproductive processes in animals. Science 124:890, 195'6. 25. PINCUS, G., et al. Studies of the biological activity of certain nor-steroids in female animals. Endrocrinology 59:695, 1956. 26. ROCK, J., PINCUS, G., and GARCIA, C. R. Effects of certain 19-nor steroids on normal human menstrual cycle. Science 124:891, 1956. 27. ROCK, J., GARCIA, C. R., and PINCUS, G. Synthetic progestins in the normal human menstrual cycle. Recent Progr. Hormone Res. 13:323, 1957. 28. ROLAND, M. Treatment of endocrine infertility with Enovid. Research in the Service of Medicine (G. D. Searle & Co.) 54:3, 1961 29. SAUNDERS, F. J., and DRILL, V. A. Some biological activities of 17-ethynyl and 17-alkyl derivatives of 17-hydroxy-estrenones. Ann. New York Acad. Sci. 71:516, 1958. 30. SAUNDERS, F. J., and ELTON, R. L. In Endocrinology of Reproduction. ED. by Lloyd, C., Acad. Press, New York, 1959, p. 227. 31. SEELEN, J. C. Complications during administration of methylestrenolone. ]. Clin. Endocrinol. 18:1137, 1958. 32. TULLNER, W. W., and HERTZ, R. High progestational activity of 19-norprogesterone. ]. Clin. Endocrinol. 12:916, 1952. 33. TYLER, E. T. Treatment of the inadequate endometrium in infertility. Calif. M. ]. 81:13,1954. 34. TYLER, E. T. "Use of Enovid and Other Agents for Improved Development of the
438
ARRATA & ARRONET
FERTILITY & STERILITY
Inadequate Luteal Phase." In Proceedings of a Symposium on Enovid. C. D., Searle & Co., Chicago, 1959, p. 15. 35. TYLER, E. T., and OLSON, H. J. Clinical use of new progestational steroids in fertility. Ann. New York Acad. Sc. 71:704, 1958. 36. VASICKA, A., and RICHTER, F. J. Effect of Enovid on the human ovary, endometrium, and vaginal smears during the preovulatory phase. Surg. Forum 10:730, 1960.
present themselves to our center with a history of infertility despite the fact that no contraception has been practiced, all the basic diagnostic procedures are performed to rule out organic disease in the genital organs or elsewhere in the reproductive system. These procedures include complete physical examination of both partners, semen analysis, basal body-temperature recordings, tubal insufHation, endometrial biopsy, postcoital tests with evaluation of the cervical changes at ovulation, hysterosalpingogram, serial vaginal cytologic studies, and if necessary, endocrine assays, dilatation and curretage, culdoscopy, and evaluation of the spermatozoal antibodies, in a routinely sequential manner.4 Once an organic cause for the infertility has been eliminated, the patients are then classified in one of the 4 following categories according to their functional ovarian status: 1. Ovulatory Patients in whom ovulation has been occurring regularly at or around midcycle, for at least 6 consecutive menstrual cycles 2. Anovulatory Patients in whom there has been no evidence of normal ovulation for at least 6 consecutive months, regardless of clinical menstrual pattern 3. Subovulatory Patients in whom normal ovulation does not occur in at least 2 of 6 consecutive menstrual cycles These 3 groups are diagnosed by evaluating the monthly basal bodytemperature recordings; at least 2 endometrial biopsies are performed during the 6-month period. Urinary pregnanediol and glucosamine determinations, serial vaginal cytologic studies, and spinnacity are confirmatory. 4. Luteal-phase inadequacy In patients in this category, the condition is diagnosed by evaluating basal body-temperature recordings, endometrial
WHEN A COUPLE
From the Infertility Center, Department of Obstetrics and Gynecology, Royal Victoria Hospital, and McGill University, Montreal, Canada. Presented at the lIth Annual Meeting of the Canadian Society for the Study of Fertility, Vancouver, B. C., Canada, June 17 and 18, 1964. The Enovid used in this stndy was supplied by G. D. Searle & Co. of Canada Ltd., Brampton, Ont., Canada.
430
.. VOL.
16, No.4, 1965
PROGESTOGENS I}.< INFERTILITY ,~
.
431
biopsies, pregnanediol values, and vaginals cells. At least 2 of the 4 test results should be abnormal for luteal-phase inadequacy to be definitely diagnosed. PRESENT STUDY ,.
Many functions and uses have been attributed to norethynodrel with mestranol (Enovid) with varying reports of success. In our center, the drug was given to infertile women with the purpose of achieving a successful rebound~phenomenon in cases of idiopathic infertility with normal ovarian function and in subovulatory and anovulatbry patients; it was also used to treat proven cases of luteal-phase inadequacy.
METHODS AND MATERIAL
Enovid was given to 72 patients; however, 4 patients did not return for treatment, 3 had 1 cycle of treatment or less, and 6 discontinued medication. Ovarian dysgenesis was found in 1 and Stein-Leventhal syndrome in 2; this reduced the number of patients in the study to 56. For the rebound phenomenon, we used 2.5 mg. norethynodrel with 0.1 mg. mestranol, or 5 mg. norethynodrel with 0.075 mg. mestranol, starting on Day 5 of the cycle and continuing for 20 days. The dose was doubled in cases of breakthrough bleeding. The compound was given for a minimum of 3 to a maximum of 9 induced menstrual cycles, with an averages of 4 to 5 cycles. The 36 patients in this group received Enovid for 167 cycles, with an average of 4.6 cycles per patient. In cases of proven luteal-phase inadequacy, the 5-mg. tablet, or the lO-mg. tablet, the latter containing 9.85 mg. norethynodrel with 0.15 mg. mestranol, was given immediately following the temperature rise in the basal bodytemperature recording for a minimum of 10 days, then resumed in the subsequent 4-5 cycles if a pregnancy test proved negative or if bleeding ensued on withdrawal of the drug. It was necessary on occasions to supplement the therapy with estrogens during the first half of the menstrual cycle. If a patient conceived while taking the drug, the therapy was carried on until at least the twelfth week of gestation, to prevent an abortion which might occur on withdrawal of the drug. This group consisted of 20 patients. Luteal-phase inadequacy was suspected when one of the four diagnostic tests had abnormal results, and was confirmed by at least one of the other three.
432
ARRATA & ARRONET
FERTILITY & STERILITY
RESULTS
Of the 56 patients, 24 (42.7%) conceived after therapy, 7 improved in ovulatory or menstrual status, and 25 showed no improvement (Table 1). Most of the failures were among the anovulatory patients with a history of primary infertility. It is interesting to note that 12 of the pregnancies (50%) occurred in the first month after withdrawal of Enovid, and 3 occurred in the second month (Fig. 1). Pregnancies occurring 1 year or more after therapy were not listed as positive results, but considered as late improvement of the original defect. In the group of 36 patients selected for attempted rebound phenomena,
Fig. 1. Incidence of pregnancies after Enovid therapy.
1
2
3
5
4
6
7 - 12
MONTHS AFTER ENOVID THERAPY
TABLE 1. Results of Enovid Therapy in 56 Infertility Patients with Regular and Irregular Menstrual Cycles Ovulatory l'leg.
Menses regulated Ovulation regulated Failures
Sub ovulatory
lrreg.
Re.q.
3 3
4
2 0
[rreg.
1 0 3
Anovulatory Reg.
[rreg.
Total
4
0 3
0 1 12
3 25
3 1
11 1
30 8
1 0
6 3
26 16
PRIMARY INFERTILITY No. of patients Conceptions
3 0
8 3
2 1
3 2
SECONDARY INFERTILITY No. of patients Conceptions
1 1
10 8
2 1
6 3
VOL.
16, No. 4, 1965
PROGESTOGENS IN
433
INFERTILITY
13 patients (36%) conceived (Table 2). Most of these were in the subovulatory group, with 7 pregnancies in 11 patients. The anovulatory patients showed improvement in only 28.6% of cases. There were 75% failures in the ovulatory group, but the statistical significance of these results is questionable because of the small sample. In the group of 20 patients with luteal-phase inadequacy, 11 (55%) conceived (Table 3). There were 6 failures in that group, and 3 patients improved on therapy although no pregnancies ensued. Of the 11 pregnancies resulting after treatment of the luteal-phase inadequacy, 5 (45.4%) ended in live births, 1 (9.2%) was ectopic, and 5 (45.4%) ended in abortions. Perhaps the low salvage rate might be attributed to the effect of the compound on the endometrium (arrest in development of the glandular component), rendering it unfavorable for nidation of the fertilized ovum. COMMENT The Rebound Phenomenon
An increase in the fertility potential has been noticed in many patients after withdrawal of progestogens taken for contraception. This interesting TABLE 2. Rebound after Enovid Therapy Cyrles No. of Ovulation status
Ovulatory Subovulatory Anovulatory TOTAL
patient.~
4 11
21 36
Range per patient
2-4 3-8 3-9 2-9
Total
Pl'egnanrie,.
Ovulation
Faihtre .•
1 7 5 13
2 1 3
3 2 15 20
12 49 106 167
TABLE 3. Results of Envoid Therapy in Luteal-Phase Inade.quacy (LPI) Group Cycles
Test
Basal body temperature Endometrial biopsy Urinary pregnanediol Vaginal smears TOTAL
No. of patients
7 8 2 3 20
Ran.qe per patient
2-6 1-10 2-5 3-8 1-10
Total
24 32 7 16 79
LPI corLPI rected and corrected pregnancy Failures
1 1 1 3
5 5 1
1 2 1 2
11
6
434
ARRATA & ARRONET
FERTILITY
& STERILlTY
phenomenon was first reported by Rock et al.;26, 27 Subsequent studies supported and contradicted their finding. 16 , 18,28,35 Among their diverse gonadal effects, progesterones suppress pituitary function. Vasicka and Richter proved that Enovid does not influence FSH, since recently stimulated follicles are present in abundance, but inhibits the luteinizing hormone, resulting in the arrest of final stages of follicular maturation, and thus preventing ovulation. Whether Enovid prevents adequate release of LH from the pituitary or inhibits its formation by the gland is debatable. If progesterone prevents release of the gonadotropins, these will accumulate during progesterone administration. When the drug is withdrawn, their sudden release may trigger ovulation in anovulatory patients, regulate it in subovulatory cases, or cause multiple ovulation with more than one ovum available during one menstrual cycle. Should the progesterone effect be inhibition of pituitary gonadotropin formation, this period of physiologic rest might be followed later by a betterfunctioning gland. Such an assumption could only be confirmed by qualitative LH bioassays. Although progestins do not supposedly affect the ovary directly, but only through the mediation of the pituitary gland, their action on the endometrium is most probably direct action. Luteal-Phase Inadequacy
The introduction of luteal-phase inadequacy as a cause of infertility has aroused much interest. There have been many reports as to its causes and diagnosis, and many conflicting opinions as to modes of treatment and their results.7, lr" 17, 19,21,22,33,35 We have classified luteal phase inadequacy as physiologic, organic, and functional. Physiologic inadequacy would be due to the postpartum state and menopause. Organic inadequacy would be due to the inability of endometrium to respond adequately to normal hormonal stimuli, because of developmental inadequacy, inflammation, or sclerosis, or due to ovarian insufficiency, in which the deficient hormonal stimulus is unable to elicit an adequate response in a normal endometrium, because of ovarian inflammation, tumors, or other causes of ovarian insufficiency. Functional inadequacy might be due to nutritional insufficiencies, intoxications, systemic diseases, or endocrinopathies such as those produced by psychogenic or neurogenic factors, pituitary insufficiency, hypo- or hyperthyroidism, or adrenal hyperfunction.
VOL.
16, No.4, 1965
PROGESTOGENS IN INFERTILITY
435
Diagnostic Criteria BASAL BODY TEMPERATURE. The presence of luteal-phase inadequacy is suspected if basal body temperature shows (1) a gradual rise at the time of ovulation, (2) a short luteal phase lasting less than 10 days, (3) an unsustained, down-slanting postovulatory phase, and (4) a drop to the preovulatory level for any 2 recordings during the luteal phase. ENDOMETRIAL BIOPSY. Biopsy is performed on or around Day 25 of the menstrual cycle. The specimen is dated and then correlated with ovulation time as determined by the basal body-temperature chart, and with the onset of the next menses. 23 We consider a delay of more than 2 days in endometrial development in relation to ovulation or to the onset of the next menses as a sign of luteal-phase inadequacy. URINARY PREGNANEDIOL. The average values for pregnanediol in our laboratory vary from 2 to 7 mg./24 hr. during a normal luteal phase. 20 Readings of 2 mg. or less per 24 hr. at any time during the progestational phase are good evidence of an inadequate luteal phase. VAGINAL SMEAR. Taking vaginal smears is an adequate method of determining and confirming poor luteal function. One reading is usually unreliable; a good test should include a series of smears taken during the second half of the menstrual cycle, so that the actual sequence of events involving the vaginal cells' desquamation could be properly evaluated. 5
DISCUSSION
A Dutch anatomist, Regner De Graaf, was the first to publish a description of the corpus luteum, in 1672, and the earliest illustration of that organ is seen in his plate of the cow's ovary.10 In 1898, the French histologist Prenant suggested that the corpus luteum is an organ of internal secretion. Two years later, the embryologist Gustav Born conceived the idea that the specific endocrine function of the corpus luteum is to protect the early embryo and facilitate its implantation; in 1903, his former student Fraenkel showed that removal of the corpora lutea of rabbits, early in pr~gnancy, invariably caused the embryos to disappear. I • 8 In 1910, Ancel and Bouin described the secretory changes of the rabbit's endometrium under the influence of the corpus luteum. 8 In 1929, Corner and Allen proved that the hormone progesterone is present in lipoid extracts of the corpus luteum, D and further purified preparations were isolated in 1931 and 1932. After the establishment of the structural formula and the synthesis of pure progesterone in 1934,3 a 20-year period followed that brought controversies
436
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concerning the role of progesterone in the maintenance of pregnancies and abortions. However, in the early 1950's, interest was aroused again by the discovery of compounds similar or related to progesterone/I, 32 and by their gonadal effects, especially inhibition of ovulation through the mediation of the pituitary gland. 6 , 14, 16, ~4-27, 29 Norethynodrel with mestranol (Enovid) was one of the earliest progestogens to be tested in this field. Numerous excellent reports dealing in detail with the chemistry, animal and human pharmacologic activities, and toxicity of norethynodrel are available. I:!, 13, 29-31 CONCLUSIONS
1. Norethynodrel with mestranol (Enovid) was effective in regulating ovulation and consequently improving the pregnancy rate for patients in whom ovulation, although present, was irregular. 2. Enovid was found successful in treating luteal-phase inadequacy. The pregnancy outcome was 55%, although 45.4% of these pregnancies terminated in abortions. 3. Little success was achieved in treating anovulatory patients, most of whom had primary infertility; some beneficial effect was achieved in cases of secondary infertility. 4. Statistical evaluation of results in the normal ovulatory group was not possible because of the size of the sample. Royal Victoria Hospital Montreal 2, Canada
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