FERTILITY AND STERILITY Copyright © 1979 The American Fertility Society
Vol. 32, No.5, November 1979 Printed in U.s.A.
LUTEAL PHASE DEFECTS
WILLIAM C. ANDREWS, M.D.
Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia 23507
Luteal phase defects are characterized by deficient steroidogenesis (primarily of progesterone) during the luteal phase of the cycle, with resultant inadequate development of the endometrium for secure implantation of fertilized ova. Clinically, this is significant in infertility, being the apparent etiologic factor in 3.5% of infertility cases l and in 35% of repeated first-trimester abortions. 2 The etiology, diagnosis, treatment, and even the existence of this condition are matters of considerable debate. These issues are discussed from the clinical viewpoint.
tory effect of elevated prolactin on luteal function in normally menstruating women. Experimentally induced elevation of prolactin levels resulted in a shortening of the hyperthermic phase and a reduction of progesterone secretion by the corpus luteum. Del Pozo et a1. 9 reported an adequate ovulatory LH surge in three women with elevated prolactin levels and an inadequate luteal phase. This finding makes it unlikely that spontaneous luteinization occurred in the absence of ovulation in these patients. They postulate, therefore, that the control of progesterone synthesis by LH during the postovulatory period may be impaired by.elevated levels of circulating prolactin. Muhlenstedt et al. l2 have reported finding slightly elevated prolactin levels in 7Cffo of patients with a short luteal phase, and normalization of both the Iuteal phase and prolactin by treatment with bromocriptine, 2.5 mg twice daily. However, oversuppression of prolactin to less than 5 ng/ml was followed by deficient luteinization. Del Pozo et al. 9 reported improvement in luteal phase progesterone production and conception in five of eight infertile women with luteal phase deficiencies and hyperprolactinemia treated with bromocriptine. An elevated prolactin level, therefore, may be an important cause of luteal insufficiency, perhaps related to impairment of LH stimulation. The seeming paradox that luteal insufficiency is also associated with inadequate prolactin levels may be explained by the importance of prolactin for activation of the 3f3-hydroxysteroid dehydrogenase enzyme in the ovary. This enzyme allows the luteal cells to synthesize progesterone. The question has been raised as to whether the uterus, through prostaglandin production, might influence corpus luteum function. Pharris and Wyngarden~3 described experimental work in the rat which indicated that endometrial release of prostaglandins was responsible for corpus luteum
ETIOLOGY
A variety of factors appear capable of producing an inadequately functioning corpus luteum. Ovarian factors may account for a small percentage of patients with luteal phase defects. l A majority of these cases, however, appear to be due to problems of the pituitary-hypothalamic axis. 3 Suboptimal levels of follicle-stimulating hormone early in the cycle,4 an inadequate luteinizing hormone (LH) surge,S or inadequate tonic LH6 independently or collectively may produce this condition. These factors have been discussed in more detail in a previous article by Jones l in Modern Trends, and the biochemistry in another article by the same author.7 An additional factor, hyperprolactinemia, has more recently been described. The correlation of elevated serum prolactin levels in some patients with deficient corpus luteum function was first reported by Wenner. s Prolactin is necessary for maintenance of luteal function in some experimental animals,9 and McNatty et al,l° have reported that the synthesis of progesterone by human granulosa cells in vitro is dependent on an adequate prolactin concentration in the culture medium. Delvoye et al. l l demonstrated an inhibi-
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ANDREWS
regression and that failure of prostaglandin release after hysterectomy could be responsible for a persistent corpus luteum. A decrease in blood progesterone levels in cycling and pregnant rhesus monkeys receiving prostaglandin F2 a for a 5- to 7-day period has been reported,14 but two studies in humans 15, 16 revealed no luteolytic action as determined by serum progesterone measurements or by effect on the menstrual cycle. Luteal phase defects may also have an iatrogenic etiology. Garcia et al. 17 reported a group of 86 anovulatory women treated with clomiphene, 43 of whom were found to have a luteal phase defect in cycles with clomiphene-induced ovulation. This probably represents an inadequate gonadotropin response to clomiphene therapy rather than a direct effect of the medication. Synthetic progestins, such as medroxyprogesterone acetate, have been shown to be luteolytic in humans 18 and could, theoretically at least, produce a luteal phase inadequacy. Keller et al. 19 have reported the first instance of infertility associated with an endometrial progesterone receptor defect. This heritable defect resembles a luteal phase defect if the diagnosis is made by endometrial biopsy, as the endometrium is unable to respond to progesterone. Normal serum progesterone assays and no response to administered progesterone confirm the diagnosis. This unusual cause of infertility, although clinically extremely rare and therefore relatively unimportant, nevertheless confirms the assumption that the progesterone effect upon the endometrium is important for normal fertility. DIAGNOSIS
The diagnosis of luteal phase insufficiency may be suggested by an abbreviated thermal shift on the basal body temperature chart or a slowly rising temperature during the luteal phase. These observations can by no means establish the diagnosis, as the thermogenic response differs with individuals, as does the accuracy of temperature taking. The most frequently used method of diagnosing luteal phase defects is by endometrial biopsy performed 1 or 2 days prior to the succeeding menses20 and dated according to the criteria of Noyes et al,21 A biopsy found to be 2 or more days out of phase suggests the diagnosis, but it must be confirmed by a similarly timed biopsy in a subsequent cycle. The change must be consistent and repetitive to establish the diagnosis. Endometrial biopsies obtained
November 1979 after the onset of menses are unsatisfactory for accurate dating. Good correlation of endometrial biopsies and daily serum progesterone assays has been reported. 22 Concerns that a premenstrual endometrial biopsy might interrupt an early pregnancy appear to be unfounded. Hughes 23 has reported statistical evidence suggesting that the biopsy may even be therapeutic by possibly stimulating a better decidual reaction. Karow et al,24 found an abortion incidence of only 6.8% for pregnancies occurring during the cycle of endometrial biopsy, as compared with the accepted incidences of 10% to 13% for apparently normal women and 21% for infertility patients. Other investigators25 ,26 in recent years have questioned the accuracy of endometrial dating for estimating progesterone production and luteal phase adequacy, and recommend serum progesterone determinations by radioimmunoassay. Shepard and Senturia26 found a correlation between biopsy findings and serum progesterone in only 75% of 53 cycles in which both were obtained. For a group in which the time of ovulation could be established with reasonable accuracy, a correlation of 89% was found. Shepard and Senturia questioned the significance of a deficient endometrium as a predictor of infertility. Assessment of ovarian progesterone secretion by urinary pregnanediol determinations is subject to errors resulting from the wide individual variability of the proportion of progesterone that is metabolized and excreted in the urine as pregnanediol. Fifteen to seventy-seven per cent of progesterone entering the peripheral circulation is found in urine, and approximately one-half of this proportion is in the form of pregnanediol conjugates. Urinary pregnanediol is not clinicaliy applicable as an assay of luteal function.27 There is also debate as to what values of serum progesterone indicate normal luteal function. Israel et al,28 reported in 1972 that a concentration of 3 ng/ml or greater of progesterone during the midluteal phase indicated ovulation. Ross et al,29 reported a rise in the basal body temperature with progesterone levels of2.5 ng/ml but concluded that 5 ng/ml represented the lower limits of normal in the midluteal phase. Radwanska and Swyer30 found midluteal phase progesterone levels of less than 10 ng/ml in 60% of women with a hormonal cause of infertility. Only 10% of their patients with a nonhormonal cause for infertility demonstrated a value below this level. They concluded that a concentration of 10 ng/ml represented the demar-
LUTEAL PHASE DEFECTS
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cation between adequate and inadequate luteal function. Abraham et al. 31 have questioned the value of a single determination and found progesterone levels greater than 3 ng/ml in the midluteal phase in seven "abnormal" cycles. They advocate three determinations obtained approximately 4, 6, and 8 days prior to the next expected menstrual period, and found that, in "normal" cycles, the sum of these three determinations was over 15 ng/ml, whereas the total value in abnormal cycles fell below 15 ng/ml. Serial progesterone determinations throughout the luteal phase would provide the most accurate determination of luteal function, but expense and inconvenience preclude this test for clinical use. The use ofthree well-timed assays as suggested by Abraham et al. 31 appears to be a reasonable compromise, although more expensive than the endometrial biopsy approach. Endometrial biopsy properly timed and properly diagnosed presents a picture of the end product ofluteal function, namely the endometrium in which the egg must be implanted. Endometrial biopsy also provides additional important information about the endometrium, including endometritis, tuberculosis screening, and the recently described progesterone receptor defect. CUNICAL SIGNIFICANCE
The clinical significance of luteal phase defects is their possible etiologic role in infertility and repeated first-trimester abortion. IsraeJ32 found luteal phase defects in 19% of 406 fertile women on the basis of a single endometrial biopsy. When diagnosed by repeated endometrial biopsy, luteal phase defects were found by Jones 1 in 3.5% of her infertility patients. Soules et al. 33 have reported 16 infertile patients with a diagnosis ofluteal phase defects established by endometrial biopsy with an average 5- to 6-day deficiency of endometrial development. Nine ofthe patients also had a history of previous miscarriage. Treatment was primarily accomplished with progesterone vaginal suppositories, 25 mg twice daily starting on the 3rd day of basal body temperature elevation and continuing until menstruation or a positive pregnancy test, in which event the progesterone supplementation was changed to 17-hydroxyprogesterone caproate, 250 mg/week until 12 to 20 weeks of gestation. One patient received progesterone intramuscularly and one received clomiphene. One who did not
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conceive received human chorionic gonadotropin (hCG), 4000 units intramuscularly every 3rd day. Eight of these patients (50%) achieved successful term pregnancies, seven of whom had been treated with progesterone. The eight patients who did not conceive were older with a longer duration of infertility, and more had additional infertility factors. Three additional pregnancies were achieved with progesterone supplementation in this study, two in infertility patients undergoing ovulation induction with clomiphene who were found to have luteal phase deficiencies and one with a history of documented habitual abortion whose luteal phase defect was diagnosed by only one endometrial bi0psy and hence was excluded from the series. Jones 34 has reported a 46% successful pregnancy rate in 33 women similarly diagnosed and treated with progesterone administered either vaginally or by intramuscular injection. A subgroup of luteal phase defects appears to exist in anovulatory women treated with clomiphene. Of a group of 86 such women reported by Garcia et al.p 43 showed a good progestational endometrium and 43 had evidence of a luteal phase defect. Of those patients with an endometrium adequately developed, 56% became pregnant with 17% aborting. Of the women with untreated luteal phase defects, only 23% conceived and 8 of 10 aborted. Correction of the luteal phase defect was attempted in 27 of the patients by the various methods listed in Table 1. Nineteen responded to treatment with adequate endometrial development and eight failed to respond. Of the nineteen women who responded, nine became pregnant with none aborting. Of those with clomipheneinduced ovulation whose endometrium remained inadequate in spite of hCG or progesterone treatment, only three conceived and all aborted. Luteal phase defects were found by Jones and Delfs2in 35% of a group of 74 women with repeated fetal wastage. In a study by Tho et al. 35 of 100 couples with repeated fetal wastage, genetic disorders were found in 25 couples and Mullerian abnormalities in 15. Twenty-three couples were found to have endometrial asynchrony or retarded endometrial development as the sole abnormality, and twenty-two of these were treated with pre implantation progesterone suppositories. The remaining couple was treated with clomiphene and luteal progesterone. Of these 23 treated patients, 21 (91%) subsequently carried their pregnancies to term. In 37 couples no detectable abnormality was found, and 22 of these 37 couples in
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ANDREWS
TABLE 1. Response to Therapy in Twenty-Seven Patients with Luteal Phase Defect during Clomiphene Therapya Improved (19 patients) Therapy
Total no. of patients No pregnancy
Not improved (8 patients)
Pregnancy (abortions)
No pregnancy
Pregnancy (abortions)
Progesterone suppositories hCG hCG + progesterone suppositories
14 12
6 4
6 (0) 2 (0)
1 4
1(1) 2 (2)
1
0
1 (0)
0
0(0)
Total therapy
27
10
9 (0)
5
3 (3)
After clomiphene therapy
18
5 (0)
aFrom Garcia et alP
the unknown group were treated empirically with tetracycline to eliminate the possibility of T-mycoplasma infection. Pregnancy was then permitted and postimplantation progesterone suppositories were initiated as soon as the pregnancy test was positive. Seventy-three per cent of these patients subsequently carried their pregnancies to term. Of the 15 untreated patients who participated in the early part of the study, 7 (47%) subsequently had a successful outcome. Lower pregnanediol levels have been reported in pregnancies ending in abortion, although whether this is a primary or secondary event in the process is debatable. Shearman and Garrett36 reported a double-blind study of the use of 17-hydroxyprogesterone in the treatment of habitual abortion and found no significant differences between the outcome in patients receiving 17-hydroxyprogesterone and those receiving placebos. Unfortunately, none of these patients received progesterone supplementation before the 7th week of pregnancy, which would seem 6 weeks too late if this defect is present from the onset of the luteal phase. Klopper and MacN aughton37 performed a similar study using an oral progestin, but again did not start therapy until the 7th to 10th week of gestation, and also found no difference in outcome. A similar study with comparable results was performed in the United States by Goldzieher 38 using medroxyprogesterone acetate, which unfortunately has been found to be luteolytic. These investigators also did not start the medication until after the pregnancy had progressed several weeks.
TREATMENT
The most frequently employed treatment of luteal phase defects has been substitutional progesterone therapy. Started 3 or 4 days after ovulation, this can be administered as progesterone in
oil, 12.5 mg intramuscularly daily, or as progesterone vaginal suppositories, 25 mg twice daily. This dosage produces serum levels of progesterone compatible with those found in the normal cycle. Substitutional therapy is continued until the onset of menses or, in the absence of menses, a serum pregnancy test can be obtained; if the test is positive, substitutional therapy is continued until the 12th week of pregnancy. The adequacy of the replacement therapy should be monitored with endometrial biopsy 1 or 2 days prior to expected menses in a treatment cycle or by serum progesterone determinations. If a higher dose of progesterone is needed, progesterone therapy should be stopped on the calculated 12th postovulatory day to avoid induction of pseudopregnancy and artificial delay of menses. An alternative method of substitutional therapy involves the use of 17-hydroxyprogesterone caproate, 250 mg intramuscularly administered 3 days after the estimated time of ovulation. If menses do not occur within 3 days of the expected time, a serum pregnancy test should be obtained and, if positive, 17-hydroxyprogesterone caproate continued on a weekly basis to 12 weeks of gestation. Stimulation of the corpus luteum by hCG has been advocated as another therapeutic approach to luteal phase defects. The number of reported cases is small. Jones et aJ.22 reported treating two patients for luteal phase defects with 2500 IU ofhCG given on the 4th, 6th, 8th, and 10th postovulatory days, with satisfactory enhancement of serum progesterone values and correction of the histologic pattern in the endometrial biopsy in one of these women. In the patient who did not respond, the dosage was subsequently increased to 5000 IU ofhCG given on a similar schedule in the succeeding cycle. Although pregnancy occurred, progesterone values were found to be lower than normal. It was concluded that the corpus luteum was partially resistant to hCG. A corpus lute urn which cannot be "rescued" by hCG might therefore be
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associated with first-trimester abortion. Vnder such circumstances hCG therapy is ineffective and progesterone supplementation is necessary. One infertile patient with a luteal phase defect was treated by Soules et al.33 with 4,000 IV ofhCG every other day, but p.regnancy was not achieved. Twelve patients with luteal phase defects during clomiphene therapy were treated by Garcia et al. 17 with hCG and in six of these the defect was corrected; two pregnancies were established which progressed to term. In six others, the defect was unrepaired and the two pregnancies which occurred ended in spontaneous abortion. The dosage employed was 10,000 IV intramuscularly at the time of estimated ovulation or 5,000 IV intramuscularly at the time of ovulation and 5,000 IV intramuscularly 5 days later. Clomiphene has been proposed as another treatment modality for luteal phase defects with the assumption that clomiphene produces a rise in gonadotropin levels. Garcia et al. 17 reported treating 26 patients for luteal phase defects with clomiphene citrate. Eleven of these patients seemed to improve after clomiphene therapy as evidenced by endometrial histology. Two of these eleven women became pregnant and neither aborted. Fifteen patients continued to show abnormalities of endometrial maturation; th.ree of these conceived and all three aborted. Thus, 2 of 26 patients with luteal phase defects treated by clomiphene in this study achieved successful pregnancy. These figures can be compared with the rates of 46% and 50%, respectively, reported by Jones 34 and by Soules et al. 33 in similar patients treated with progesterone. Quagliarello and Weiss 39 have reported clomiphene treatment of eight infertile women with repetitively short luteal phases as diagnosed by basal body temperature charts. They confirmed ovulation with a single luteal phase progesterone determination which was reported as greater than 3 ng/ml in each case, but serial progesterone determinations or endometrial biopsies were not performed to establish a diagnosis of luteal phase defect. With the dosage of 50 mg of clomiphene citrate from the 5th to the 9th day of the cycle, two of the eight patients conceived during the first cycle and the remaining six demonstrated lengthening of the luteal phase (an additional 3 to 6 days). In subsequent cycles, the dosage was increased and the treatment cycle lengthened in a stepwise fashion; five of the remaining six women became pregnant within six cycles of therapy. Whether these cases can be considered luteal
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phase defects is open to question based upon the published information. Bromocriptine, in a dosage of 5 mg daily, was used by Del Pozo et al. 9 in treating eight infertile women with luteal insufficiency and moderately elevated prolactin levels. Six of the eight patients responded with reduction of prolactin and increased serum progesterone, and five of these became pregnant. Twelve similar patients were treated by EI Mahgoub40 with bromocriptine. Seven patients developed normal luteal phase endometrium on this therapy. Clomiphene was added to the therapy of the remaining five patients on the 2nd and 6th days, and three ofthese women "responded." Six of the twelve patients became pregnant during therapy, but the author did not distinguish how many pregnancies occurred in each treatment group. Two patients with galactorrhea-amenorrhea and short luteal phases (one with a luteal phase defect noted on endometrial biopsy) after clomiphene therapy developed normal cycles with bromocriptine therapy, and one woman became pregnant on this regimen. 41 Saunders et al. 42 administered bromocriptine to 15 infertile patients with luteal phase defects and normal prolactin levels. The dosage was started as 3.75 mg daily and was increased over 6 days to 15 mg daily in divided doses for 4 months. Progesterone levels were not significantly altered. Two of the fifteen patients became pregnant, but the authors concluded that this result was coincidental. From assessment of the reported cases, and personal experience, it appea.rs that progesterone supplementation is the most effective method of t.reatment of luteal phase defects. Clomiphene or hCG together or individually can be used in the unusual patient who does not respond to progesterone. Bromocriptine appears to be therapeutic for infertile patients with luteal phase defects and elevated prolactin levels, but not for those whose prolactin levels are normal. The problem of premature labor may be an extension of the basic problem of progesterone deficiency in pregnancy. Johnson et al.4 3 have identified a group at risk by a history of (1) two spontaneous abortions, or (2) one premature delivery and one spontaneous abortion preceding the current pregnancy, or (3) two or more previous premature deliveries. In a double-blind study, they treated 18 patients with 17-hydroxyprogesterone caproate, 250 mg intramuscula.rly weekly, starting at 16 weeks. There were no premature de-
ANDREWS
506
liveries and no perinatal deaths in the treated group, as compared with 41% premature deli veries and 27% perinatal deaths in the control group. An extension of this study to 70 patients was reported at a symposium on progesterone44 with a 13% incidence of prematurity in the treated group versus 42% in the placebo group, and a 5% fetal mortality rate versus 25% in the placebo group. CONCERNS ABOUT TERATOGENICITY
The use of progesterone in pregnancy has been questioned because of reports of a possible increase in the incidence of congenital anomalies in babies born to mothers receiving estrogen-progestin combinations or progestins alone during early pregnancy. The first ofthese reports, by Gal et al.45 in 1967, showed an apparent increase in neural tube defects in infants of mothers who had taken estrogen-progestin combinations as a pregnancy test, although this was not found in a CDC study by Oakley et a1. 46 Nora and Nora47 and Nora et al.48 have reported an increased incidence of exposure to exogenous sex hormones in mothers of infants having the VACTERL syndrome (i.e., anomalies of the vertebral column; anomalies of anal, cardiac, tracheal, esophageal, and renal tissues; and limbreduction defects) as compared with a group of mothers of normal babies. A similar association with congenital heart disease was reported by Janerich et a1. 49. 50 In both of these studies, the cases were not analyzed as to which medication was given but were grouped together; a majority included the use of estrogen-progestin combinations. The largest study concerning a possible relationship of steroids to birth defects was that of Heinonen et al.,51 part ofthe American Collaborative Perinatal Study, which involved 50,282 pregnancies: 19 children with cardiovascular defects were born to 1,042 women who had received female hormones in early pregnancy, a cardiovascular malformation rate of 18.2/1,000 as compared with a rate of 7.8/1,000 in a control population-a relative risk of 2.4. When analyzed as to type of hormone exposure, no association was found with progesterone or 17hydroxyprogesterone. 52 The incidence with 17hydroxyprogesterone was reported to be 0.75 as against a background incidence of 1.0. In this study, of 404 babies with congenital heart disease, only 2 of the mothers had taken progesterone. Such an incidence, as Slone stated, "is approximately what you would expect by chance."44 This
November 1979 study also found no association between the VACTERL syndrome or limb-reduction defects and the use of hormones. In an earlier publication of the American Collaborative Perinatal Study, 53 it was reported that maternal exposure to sex steroids in both early and late gestation was associated with infant malformations in similar numbers. This finding would argue strongly against a causal relationship. In a prospective English study of oral contraception, no increase in anomalies was noted in children of patients who inadvertently took oral contraceptives during pregnancy. 54. 55 In the comparative study by Vessey and Do1l55 of contraceptive usage among women using oral contraceptives, diaphragms, and intrauterine devices, the only limb-reduction defect found was in an infant born to a mother who had ceased diaphragm usage. Many cases of congenital heart disease are of genetic origin, and none of these studies included family pedigrees. In January 1977, the Food and Drug Administration proposed labeling changes to its Obstetrics and Gynecology Advisory Committee recommending against the use of progesterone or progestins during pregnancy. The Committee unanimously voted to exclude progesterone from this labeling because of absence of evidence correlating congenital anomalies with progesterone administration. In spite of this, the Food and Drug Administration proceeded to require patient and physician labeling of progestins and progesterone, including a warning about possible teratogenicity of the compounds. 56 To bring these issues into focus and allow discussion and consideration of the evidence, The American Fertility Society in January 1978 sponsored a symposium in Washington entitled "Progesterone, Progestins, and Fetal Development."44.57 Nora, Janerich, and Slone presented their data on fetal anomalies and the use of progestins. Janerich and Slone admitted that their data did not show a causal relationship between progesterone or 17-hydroxyprogesterone and fetal anomalies. Griff T. Ross, Deputy Director of the Clinical Center at the National Institutes of Health, reviewed the correlates of normal corpus luteum function and the hormonal milieu to which the oocyte and the fetus are exposed. He pointed out that progesterone and 17-hydroxyprogesterone are naturally occurring hormones, to which the egg is exposed in much higher concentrations in antral fluid than are achieved therapeutically. At
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LUTEAL PHASE DEFECTS
least in nonhuman primates, postovulatory tubal fluid shows levels much higher than found in blood. Ross also pointed out that the second polar body is extruded after spermatozoal penetration and that there is a potential for chromosomal abnormalities to occur in a blastocyst exposed to deficiencies in concentration of progestational hormones during meiosis. He further noted that in the presence of 17a-hydroxylase deficiency, the resultant fetal exposure to high levels of endogenous progesterone results in nonanomalous phenotypic feminization regardless of endogenous androgen production. At the same symposium,44 Richard Blye of the National Institute of Child Health and Human. Development discussed the many chemical and I biologic differences between natural progesterones and the synthetic progestins. He stated that therelwas nOlapparent human adult toxicity of progesterone. 17-Hydroxyprogesterone caproate has been used in the treatment of endometrial carcinoma in doses 20 to 40 times those employed in pregnancy, without significant side effects other than local discomfort. Also at this symposium,44 Jones addressed the question of whether treating patients with repeated fetal wastage may prevent abortion but bring more abnormal fetuses to term. She analyzed the pregnancy outcome of 448 women with a history of repeated fetal wastage who subsequently delivered viable infants. One hundred and fifty-five of these mothers were treated with progesterone; the remainder were not. The congenital anomaly rates were 4.5 for the treated group and 4.2 for the untreated group. There were no limb-reduction defects in either group. For comparison, congenital anomaly rates of2.2 to 7.3 have been reported for so-called normal mothers. Franklin presented a study of the fetal outcome of 837 pregnancies in which the women received 17hydroxyprogesterone caproate, 80% of whom were started on the medication during the first trimester of pregnancy, and found no significant differences in the rate of anomalies. Sufficient questions are raised by these studies to indicate that medroxyprogesterone acetate, norethindrone, and norethindrone acetate should not be used during pregnancy. The luteolytic potential of these agents also makes them undesirable for use in the treatment ofluteal phase defects. There is no consensus that valid evidence exists to indicate that progesterone and 17-hydroxyprogesterone are teratogenic, nor is there any physiologic reason to expect them to be, since they
507
are physiologic and are used in physiologic doses. Because of the action ofthe Food and Drug Administration, however, these reports should be discussed with the patient, as well as the package insert which is given to her. This information may be supplemented and balanced by referring her to the article "Proceedings of the Symposium 'Progesterone, Progestins, and Fetal Development'" by Chez. 57 In summary, the concluding remarks by Chez57 are pertinent: "The question must be raised about the cost to patients who are denied treatment-costs in terms of their general quality oflife. Since there is statistically significant evidence that the administration of exogenous progesterone can diminish the incidence of premature labor, can diminish one cause of infertility, and can diminish one cause of spontaneous abortion, there are critical public health issues. The patient's ethics and priorities and the physician's response to these priorities constitute elements of the art of medicine." From the evidence available, the benefits of properly prescribed progesterone therapy for the proper diagnosis appear to outweigh the risks. Luteal phase defects can be considered a deficiency state, leading to infertility. Substitutional therapy with progesterone, endogenous or exogenous, has proved its effectiveness. Judicious use of progesterone in documented cases is an appropriate approach to luteal phase defects.
REFERENCES 1. Jones GS: The luteal phase defect. Fertil Steril 27:351,
1976 2. Jones GS, Delfs E: Endocrine patterns in term pregnancies following abortion. JAMA 146:1212, 1951 3. Jones GS, Madrigal-Castro V: Hormonal findings in association with abnormal corpus luteum function in the human: the luteal phase defect. Fertil Steril 21:1, 1970 4. Jones GS, Moraes-Ruehsen MD, Johanson AJ, Raita S, Blizzard RM: Elucidation of normal ovarian physiology by exogenous gonadotropin stimulation following steroid pituitary suppression. Fertil Steril 20:1, 1969 5. Strott CA, Cargille CM, Ross GT, Lipsett MB: The short luteal phase. J Clin Endocrinol Metab 30:246, 1970 6. Vande WieleRL, Bogumil J, Dyrenfurth I, Ferin M, Jewelewicz R, Warren M, Rizkallah J, Mikhail G: Mechanisms regulating the menstrual cycle in women. Recent Prog Horm Res 26:63, 1970 7. Jones GS: Luteal phase defects. In Progress in Infertility, Second Edition, Edited by SJ Behrman, RW Kistner. Boston, Little, Brown and Co, 1975, p 299 8. Wenner R: Les antiprolactines. Actual Gynecol
Vol. 32, No.5, November 1979 Printed in U.s.A.
LUTEAL PHASE DEFECTS
WILLIAM C. ANDREWS, M.D.
Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia 23507
Luteal phase defects are characterized by deficient steroidogenesis (primarily of progesterone) during the luteal phase of the cycle, with resultant inadequate development of the endometrium for secure implantation of fertilized ova. Clinically, this is significant in infertility, being the apparent etiologic factor in 3.5% of infertility cases l and in 35% of repeated first-trimester abortions. 2 The etiology, diagnosis, treatment, and even the existence of this condition are matters of considerable debate. These issues are discussed from the clinical viewpoint.
tory effect of elevated prolactin on luteal function in normally menstruating women. Experimentally induced elevation of prolactin levels resulted in a shortening of the hyperthermic phase and a reduction of progesterone secretion by the corpus luteum. Del Pozo et a1. 9 reported an adequate ovulatory LH surge in three women with elevated prolactin levels and an inadequate luteal phase. This finding makes it unlikely that spontaneous luteinization occurred in the absence of ovulation in these patients. They postulate, therefore, that the control of progesterone synthesis by LH during the postovulatory period may be impaired by.elevated levels of circulating prolactin. Muhlenstedt et al. l2 have reported finding slightly elevated prolactin levels in 7Cffo of patients with a short luteal phase, and normalization of both the Iuteal phase and prolactin by treatment with bromocriptine, 2.5 mg twice daily. However, oversuppression of prolactin to less than 5 ng/ml was followed by deficient luteinization. Del Pozo et al. 9 reported improvement in luteal phase progesterone production and conception in five of eight infertile women with luteal phase deficiencies and hyperprolactinemia treated with bromocriptine. An elevated prolactin level, therefore, may be an important cause of luteal insufficiency, perhaps related to impairment of LH stimulation. The seeming paradox that luteal insufficiency is also associated with inadequate prolactin levels may be explained by the importance of prolactin for activation of the 3f3-hydroxysteroid dehydrogenase enzyme in the ovary. This enzyme allows the luteal cells to synthesize progesterone. The question has been raised as to whether the uterus, through prostaglandin production, might influence corpus luteum function. Pharris and Wyngarden~3 described experimental work in the rat which indicated that endometrial release of prostaglandins was responsible for corpus luteum
ETIOLOGY
A variety of factors appear capable of producing an inadequately functioning corpus luteum. Ovarian factors may account for a small percentage of patients with luteal phase defects. l A majority of these cases, however, appear to be due to problems of the pituitary-hypothalamic axis. 3 Suboptimal levels of follicle-stimulating hormone early in the cycle,4 an inadequate luteinizing hormone (LH) surge,S or inadequate tonic LH6 independently or collectively may produce this condition. These factors have been discussed in more detail in a previous article by Jones l in Modern Trends, and the biochemistry in another article by the same author.7 An additional factor, hyperprolactinemia, has more recently been described. The correlation of elevated serum prolactin levels in some patients with deficient corpus luteum function was first reported by Wenner. s Prolactin is necessary for maintenance of luteal function in some experimental animals,9 and McNatty et al,l° have reported that the synthesis of progesterone by human granulosa cells in vitro is dependent on an adequate prolactin concentration in the culture medium. Delvoye et al. l l demonstrated an inhibi-
501
502
ANDREWS
regression and that failure of prostaglandin release after hysterectomy could be responsible for a persistent corpus luteum. A decrease in blood progesterone levels in cycling and pregnant rhesus monkeys receiving prostaglandin F2 a for a 5- to 7-day period has been reported,14 but two studies in humans 15, 16 revealed no luteolytic action as determined by serum progesterone measurements or by effect on the menstrual cycle. Luteal phase defects may also have an iatrogenic etiology. Garcia et al. 17 reported a group of 86 anovulatory women treated with clomiphene, 43 of whom were found to have a luteal phase defect in cycles with clomiphene-induced ovulation. This probably represents an inadequate gonadotropin response to clomiphene therapy rather than a direct effect of the medication. Synthetic progestins, such as medroxyprogesterone acetate, have been shown to be luteolytic in humans 18 and could, theoretically at least, produce a luteal phase inadequacy. Keller et al. 19 have reported the first instance of infertility associated with an endometrial progesterone receptor defect. This heritable defect resembles a luteal phase defect if the diagnosis is made by endometrial biopsy, as the endometrium is unable to respond to progesterone. Normal serum progesterone assays and no response to administered progesterone confirm the diagnosis. This unusual cause of infertility, although clinically extremely rare and therefore relatively unimportant, nevertheless confirms the assumption that the progesterone effect upon the endometrium is important for normal fertility. DIAGNOSIS
The diagnosis of luteal phase insufficiency may be suggested by an abbreviated thermal shift on the basal body temperature chart or a slowly rising temperature during the luteal phase. These observations can by no means establish the diagnosis, as the thermogenic response differs with individuals, as does the accuracy of temperature taking. The most frequently used method of diagnosing luteal phase defects is by endometrial biopsy performed 1 or 2 days prior to the succeeding menses20 and dated according to the criteria of Noyes et al,21 A biopsy found to be 2 or more days out of phase suggests the diagnosis, but it must be confirmed by a similarly timed biopsy in a subsequent cycle. The change must be consistent and repetitive to establish the diagnosis. Endometrial biopsies obtained
November 1979 after the onset of menses are unsatisfactory for accurate dating. Good correlation of endometrial biopsies and daily serum progesterone assays has been reported. 22 Concerns that a premenstrual endometrial biopsy might interrupt an early pregnancy appear to be unfounded. Hughes 23 has reported statistical evidence suggesting that the biopsy may even be therapeutic by possibly stimulating a better decidual reaction. Karow et al,24 found an abortion incidence of only 6.8% for pregnancies occurring during the cycle of endometrial biopsy, as compared with the accepted incidences of 10% to 13% for apparently normal women and 21% for infertility patients. Other investigators25 ,26 in recent years have questioned the accuracy of endometrial dating for estimating progesterone production and luteal phase adequacy, and recommend serum progesterone determinations by radioimmunoassay. Shepard and Senturia26 found a correlation between biopsy findings and serum progesterone in only 75% of 53 cycles in which both were obtained. For a group in which the time of ovulation could be established with reasonable accuracy, a correlation of 89% was found. Shepard and Senturia questioned the significance of a deficient endometrium as a predictor of infertility. Assessment of ovarian progesterone secretion by urinary pregnanediol determinations is subject to errors resulting from the wide individual variability of the proportion of progesterone that is metabolized and excreted in the urine as pregnanediol. Fifteen to seventy-seven per cent of progesterone entering the peripheral circulation is found in urine, and approximately one-half of this proportion is in the form of pregnanediol conjugates. Urinary pregnanediol is not clinicaliy applicable as an assay of luteal function.27 There is also debate as to what values of serum progesterone indicate normal luteal function. Israel et al,28 reported in 1972 that a concentration of 3 ng/ml or greater of progesterone during the midluteal phase indicated ovulation. Ross et al,29 reported a rise in the basal body temperature with progesterone levels of2.5 ng/ml but concluded that 5 ng/ml represented the lower limits of normal in the midluteal phase. Radwanska and Swyer30 found midluteal phase progesterone levels of less than 10 ng/ml in 60% of women with a hormonal cause of infertility. Only 10% of their patients with a nonhormonal cause for infertility demonstrated a value below this level. They concluded that a concentration of 10 ng/ml represented the demar-
LUTEAL PHASE DEFECTS
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cation between adequate and inadequate luteal function. Abraham et al. 31 have questioned the value of a single determination and found progesterone levels greater than 3 ng/ml in the midluteal phase in seven "abnormal" cycles. They advocate three determinations obtained approximately 4, 6, and 8 days prior to the next expected menstrual period, and found that, in "normal" cycles, the sum of these three determinations was over 15 ng/ml, whereas the total value in abnormal cycles fell below 15 ng/ml. Serial progesterone determinations throughout the luteal phase would provide the most accurate determination of luteal function, but expense and inconvenience preclude this test for clinical use. The use ofthree well-timed assays as suggested by Abraham et al. 31 appears to be a reasonable compromise, although more expensive than the endometrial biopsy approach. Endometrial biopsy properly timed and properly diagnosed presents a picture of the end product ofluteal function, namely the endometrium in which the egg must be implanted. Endometrial biopsy also provides additional important information about the endometrium, including endometritis, tuberculosis screening, and the recently described progesterone receptor defect. CUNICAL SIGNIFICANCE
The clinical significance of luteal phase defects is their possible etiologic role in infertility and repeated first-trimester abortion. IsraeJ32 found luteal phase defects in 19% of 406 fertile women on the basis of a single endometrial biopsy. When diagnosed by repeated endometrial biopsy, luteal phase defects were found by Jones 1 in 3.5% of her infertility patients. Soules et al. 33 have reported 16 infertile patients with a diagnosis ofluteal phase defects established by endometrial biopsy with an average 5- to 6-day deficiency of endometrial development. Nine ofthe patients also had a history of previous miscarriage. Treatment was primarily accomplished with progesterone vaginal suppositories, 25 mg twice daily starting on the 3rd day of basal body temperature elevation and continuing until menstruation or a positive pregnancy test, in which event the progesterone supplementation was changed to 17-hydroxyprogesterone caproate, 250 mg/week until 12 to 20 weeks of gestation. One patient received progesterone intramuscularly and one received clomiphene. One who did not
503
conceive received human chorionic gonadotropin (hCG), 4000 units intramuscularly every 3rd day. Eight of these patients (50%) achieved successful term pregnancies, seven of whom had been treated with progesterone. The eight patients who did not conceive were older with a longer duration of infertility, and more had additional infertility factors. Three additional pregnancies were achieved with progesterone supplementation in this study, two in infertility patients undergoing ovulation induction with clomiphene who were found to have luteal phase deficiencies and one with a history of documented habitual abortion whose luteal phase defect was diagnosed by only one endometrial bi0psy and hence was excluded from the series. Jones 34 has reported a 46% successful pregnancy rate in 33 women similarly diagnosed and treated with progesterone administered either vaginally or by intramuscular injection. A subgroup of luteal phase defects appears to exist in anovulatory women treated with clomiphene. Of a group of 86 such women reported by Garcia et al.p 43 showed a good progestational endometrium and 43 had evidence of a luteal phase defect. Of those patients with an endometrium adequately developed, 56% became pregnant with 17% aborting. Of the women with untreated luteal phase defects, only 23% conceived and 8 of 10 aborted. Correction of the luteal phase defect was attempted in 27 of the patients by the various methods listed in Table 1. Nineteen responded to treatment with adequate endometrial development and eight failed to respond. Of the nineteen women who responded, nine became pregnant with none aborting. Of those with clomipheneinduced ovulation whose endometrium remained inadequate in spite of hCG or progesterone treatment, only three conceived and all aborted. Luteal phase defects were found by Jones and Delfs2in 35% of a group of 74 women with repeated fetal wastage. In a study by Tho et al. 35 of 100 couples with repeated fetal wastage, genetic disorders were found in 25 couples and Mullerian abnormalities in 15. Twenty-three couples were found to have endometrial asynchrony or retarded endometrial development as the sole abnormality, and twenty-two of these were treated with pre implantation progesterone suppositories. The remaining couple was treated with clomiphene and luteal progesterone. Of these 23 treated patients, 21 (91%) subsequently carried their pregnancies to term. In 37 couples no detectable abnormality was found, and 22 of these 37 couples in
504
November 1979
ANDREWS
TABLE 1. Response to Therapy in Twenty-Seven Patients with Luteal Phase Defect during Clomiphene Therapya Improved (19 patients) Therapy
Total no. of patients No pregnancy
Not improved (8 patients)
Pregnancy (abortions)
No pregnancy
Pregnancy (abortions)
Progesterone suppositories hCG hCG + progesterone suppositories
14 12
6 4
6 (0) 2 (0)
1 4
1(1) 2 (2)
1
0
1 (0)
0
0(0)
Total therapy
27
10
9 (0)
5
3 (3)
After clomiphene therapy
18
5 (0)
aFrom Garcia et alP
the unknown group were treated empirically with tetracycline to eliminate the possibility of T-mycoplasma infection. Pregnancy was then permitted and postimplantation progesterone suppositories were initiated as soon as the pregnancy test was positive. Seventy-three per cent of these patients subsequently carried their pregnancies to term. Of the 15 untreated patients who participated in the early part of the study, 7 (47%) subsequently had a successful outcome. Lower pregnanediol levels have been reported in pregnancies ending in abortion, although whether this is a primary or secondary event in the process is debatable. Shearman and Garrett36 reported a double-blind study of the use of 17-hydroxyprogesterone in the treatment of habitual abortion and found no significant differences between the outcome in patients receiving 17-hydroxyprogesterone and those receiving placebos. Unfortunately, none of these patients received progesterone supplementation before the 7th week of pregnancy, which would seem 6 weeks too late if this defect is present from the onset of the luteal phase. Klopper and MacN aughton37 performed a similar study using an oral progestin, but again did not start therapy until the 7th to 10th week of gestation, and also found no difference in outcome. A similar study with comparable results was performed in the United States by Goldzieher 38 using medroxyprogesterone acetate, which unfortunately has been found to be luteolytic. These investigators also did not start the medication until after the pregnancy had progressed several weeks.
TREATMENT
The most frequently employed treatment of luteal phase defects has been substitutional progesterone therapy. Started 3 or 4 days after ovulation, this can be administered as progesterone in
oil, 12.5 mg intramuscularly daily, or as progesterone vaginal suppositories, 25 mg twice daily. This dosage produces serum levels of progesterone compatible with those found in the normal cycle. Substitutional therapy is continued until the onset of menses or, in the absence of menses, a serum pregnancy test can be obtained; if the test is positive, substitutional therapy is continued until the 12th week of pregnancy. The adequacy of the replacement therapy should be monitored with endometrial biopsy 1 or 2 days prior to expected menses in a treatment cycle or by serum progesterone determinations. If a higher dose of progesterone is needed, progesterone therapy should be stopped on the calculated 12th postovulatory day to avoid induction of pseudopregnancy and artificial delay of menses. An alternative method of substitutional therapy involves the use of 17-hydroxyprogesterone caproate, 250 mg intramuscularly administered 3 days after the estimated time of ovulation. If menses do not occur within 3 days of the expected time, a serum pregnancy test should be obtained and, if positive, 17-hydroxyprogesterone caproate continued on a weekly basis to 12 weeks of gestation. Stimulation of the corpus luteum by hCG has been advocated as another therapeutic approach to luteal phase defects. The number of reported cases is small. Jones et aJ.22 reported treating two patients for luteal phase defects with 2500 IU ofhCG given on the 4th, 6th, 8th, and 10th postovulatory days, with satisfactory enhancement of serum progesterone values and correction of the histologic pattern in the endometrial biopsy in one of these women. In the patient who did not respond, the dosage was subsequently increased to 5000 IU ofhCG given on a similar schedule in the succeeding cycle. Although pregnancy occurred, progesterone values were found to be lower than normal. It was concluded that the corpus luteum was partially resistant to hCG. A corpus lute urn which cannot be "rescued" by hCG might therefore be
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associated with first-trimester abortion. Vnder such circumstances hCG therapy is ineffective and progesterone supplementation is necessary. One infertile patient with a luteal phase defect was treated by Soules et al.33 with 4,000 IV ofhCG every other day, but p.regnancy was not achieved. Twelve patients with luteal phase defects during clomiphene therapy were treated by Garcia et al. 17 with hCG and in six of these the defect was corrected; two pregnancies were established which progressed to term. In six others, the defect was unrepaired and the two pregnancies which occurred ended in spontaneous abortion. The dosage employed was 10,000 IV intramuscularly at the time of estimated ovulation or 5,000 IV intramuscularly at the time of ovulation and 5,000 IV intramuscularly 5 days later. Clomiphene has been proposed as another treatment modality for luteal phase defects with the assumption that clomiphene produces a rise in gonadotropin levels. Garcia et al. 17 reported treating 26 patients for luteal phase defects with clomiphene citrate. Eleven of these patients seemed to improve after clomiphene therapy as evidenced by endometrial histology. Two of these eleven women became pregnant and neither aborted. Fifteen patients continued to show abnormalities of endometrial maturation; th.ree of these conceived and all three aborted. Thus, 2 of 26 patients with luteal phase defects treated by clomiphene in this study achieved successful pregnancy. These figures can be compared with the rates of 46% and 50%, respectively, reported by Jones 34 and by Soules et al. 33 in similar patients treated with progesterone. Quagliarello and Weiss 39 have reported clomiphene treatment of eight infertile women with repetitively short luteal phases as diagnosed by basal body temperature charts. They confirmed ovulation with a single luteal phase progesterone determination which was reported as greater than 3 ng/ml in each case, but serial progesterone determinations or endometrial biopsies were not performed to establish a diagnosis of luteal phase defect. With the dosage of 50 mg of clomiphene citrate from the 5th to the 9th day of the cycle, two of the eight patients conceived during the first cycle and the remaining six demonstrated lengthening of the luteal phase (an additional 3 to 6 days). In subsequent cycles, the dosage was increased and the treatment cycle lengthened in a stepwise fashion; five of the remaining six women became pregnant within six cycles of therapy. Whether these cases can be considered luteal
505
phase defects is open to question based upon the published information. Bromocriptine, in a dosage of 5 mg daily, was used by Del Pozo et al. 9 in treating eight infertile women with luteal insufficiency and moderately elevated prolactin levels. Six of the eight patients responded with reduction of prolactin and increased serum progesterone, and five of these became pregnant. Twelve similar patients were treated by EI Mahgoub40 with bromocriptine. Seven patients developed normal luteal phase endometrium on this therapy. Clomiphene was added to the therapy of the remaining five patients on the 2nd and 6th days, and three ofthese women "responded." Six of the twelve patients became pregnant during therapy, but the author did not distinguish how many pregnancies occurred in each treatment group. Two patients with galactorrhea-amenorrhea and short luteal phases (one with a luteal phase defect noted on endometrial biopsy) after clomiphene therapy developed normal cycles with bromocriptine therapy, and one woman became pregnant on this regimen. 41 Saunders et al. 42 administered bromocriptine to 15 infertile patients with luteal phase defects and normal prolactin levels. The dosage was started as 3.75 mg daily and was increased over 6 days to 15 mg daily in divided doses for 4 months. Progesterone levels were not significantly altered. Two of the fifteen patients became pregnant, but the authors concluded that this result was coincidental. From assessment of the reported cases, and personal experience, it appea.rs that progesterone supplementation is the most effective method of t.reatment of luteal phase defects. Clomiphene or hCG together or individually can be used in the unusual patient who does not respond to progesterone. Bromocriptine appears to be therapeutic for infertile patients with luteal phase defects and elevated prolactin levels, but not for those whose prolactin levels are normal. The problem of premature labor may be an extension of the basic problem of progesterone deficiency in pregnancy. Johnson et al.4 3 have identified a group at risk by a history of (1) two spontaneous abortions, or (2) one premature delivery and one spontaneous abortion preceding the current pregnancy, or (3) two or more previous premature deliveries. In a double-blind study, they treated 18 patients with 17-hydroxyprogesterone caproate, 250 mg intramuscula.rly weekly, starting at 16 weeks. There were no premature de-
ANDREWS
506
liveries and no perinatal deaths in the treated group, as compared with 41% premature deli veries and 27% perinatal deaths in the control group. An extension of this study to 70 patients was reported at a symposium on progesterone44 with a 13% incidence of prematurity in the treated group versus 42% in the placebo group, and a 5% fetal mortality rate versus 25% in the placebo group. CONCERNS ABOUT TERATOGENICITY
The use of progesterone in pregnancy has been questioned because of reports of a possible increase in the incidence of congenital anomalies in babies born to mothers receiving estrogen-progestin combinations or progestins alone during early pregnancy. The first ofthese reports, by Gal et al.45 in 1967, showed an apparent increase in neural tube defects in infants of mothers who had taken estrogen-progestin combinations as a pregnancy test, although this was not found in a CDC study by Oakley et a1. 46 Nora and Nora47 and Nora et al.48 have reported an increased incidence of exposure to exogenous sex hormones in mothers of infants having the VACTERL syndrome (i.e., anomalies of the vertebral column; anomalies of anal, cardiac, tracheal, esophageal, and renal tissues; and limbreduction defects) as compared with a group of mothers of normal babies. A similar association with congenital heart disease was reported by Janerich et a1. 49. 50 In both of these studies, the cases were not analyzed as to which medication was given but were grouped together; a majority included the use of estrogen-progestin combinations. The largest study concerning a possible relationship of steroids to birth defects was that of Heinonen et al.,51 part ofthe American Collaborative Perinatal Study, which involved 50,282 pregnancies: 19 children with cardiovascular defects were born to 1,042 women who had received female hormones in early pregnancy, a cardiovascular malformation rate of 18.2/1,000 as compared with a rate of 7.8/1,000 in a control population-a relative risk of 2.4. When analyzed as to type of hormone exposure, no association was found with progesterone or 17hydroxyprogesterone. 52 The incidence with 17hydroxyprogesterone was reported to be 0.75 as against a background incidence of 1.0. In this study, of 404 babies with congenital heart disease, only 2 of the mothers had taken progesterone. Such an incidence, as Slone stated, "is approximately what you would expect by chance."44 This
November 1979 study also found no association between the VACTERL syndrome or limb-reduction defects and the use of hormones. In an earlier publication of the American Collaborative Perinatal Study, 53 it was reported that maternal exposure to sex steroids in both early and late gestation was associated with infant malformations in similar numbers. This finding would argue strongly against a causal relationship. In a prospective English study of oral contraception, no increase in anomalies was noted in children of patients who inadvertently took oral contraceptives during pregnancy. 54. 55 In the comparative study by Vessey and Do1l55 of contraceptive usage among women using oral contraceptives, diaphragms, and intrauterine devices, the only limb-reduction defect found was in an infant born to a mother who had ceased diaphragm usage. Many cases of congenital heart disease are of genetic origin, and none of these studies included family pedigrees. In January 1977, the Food and Drug Administration proposed labeling changes to its Obstetrics and Gynecology Advisory Committee recommending against the use of progesterone or progestins during pregnancy. The Committee unanimously voted to exclude progesterone from this labeling because of absence of evidence correlating congenital anomalies with progesterone administration. In spite of this, the Food and Drug Administration proceeded to require patient and physician labeling of progestins and progesterone, including a warning about possible teratogenicity of the compounds. 56 To bring these issues into focus and allow discussion and consideration of the evidence, The American Fertility Society in January 1978 sponsored a symposium in Washington entitled "Progesterone, Progestins, and Fetal Development."44.57 Nora, Janerich, and Slone presented their data on fetal anomalies and the use of progestins. Janerich and Slone admitted that their data did not show a causal relationship between progesterone or 17-hydroxyprogesterone and fetal anomalies. Griff T. Ross, Deputy Director of the Clinical Center at the National Institutes of Health, reviewed the correlates of normal corpus luteum function and the hormonal milieu to which the oocyte and the fetus are exposed. He pointed out that progesterone and 17-hydroxyprogesterone are naturally occurring hormones, to which the egg is exposed in much higher concentrations in antral fluid than are achieved therapeutically. At
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LUTEAL PHASE DEFECTS
least in nonhuman primates, postovulatory tubal fluid shows levels much higher than found in blood. Ross also pointed out that the second polar body is extruded after spermatozoal penetration and that there is a potential for chromosomal abnormalities to occur in a blastocyst exposed to deficiencies in concentration of progestational hormones during meiosis. He further noted that in the presence of 17a-hydroxylase deficiency, the resultant fetal exposure to high levels of endogenous progesterone results in nonanomalous phenotypic feminization regardless of endogenous androgen production. At the same symposium,44 Richard Blye of the National Institute of Child Health and Human. Development discussed the many chemical and I biologic differences between natural progesterones and the synthetic progestins. He stated that therelwas nOlapparent human adult toxicity of progesterone. 17-Hydroxyprogesterone caproate has been used in the treatment of endometrial carcinoma in doses 20 to 40 times those employed in pregnancy, without significant side effects other than local discomfort. Also at this symposium,44 Jones addressed the question of whether treating patients with repeated fetal wastage may prevent abortion but bring more abnormal fetuses to term. She analyzed the pregnancy outcome of 448 women with a history of repeated fetal wastage who subsequently delivered viable infants. One hundred and fifty-five of these mothers were treated with progesterone; the remainder were not. The congenital anomaly rates were 4.5 for the treated group and 4.2 for the untreated group. There were no limb-reduction defects in either group. For comparison, congenital anomaly rates of2.2 to 7.3 have been reported for so-called normal mothers. Franklin presented a study of the fetal outcome of 837 pregnancies in which the women received 17hydroxyprogesterone caproate, 80% of whom were started on the medication during the first trimester of pregnancy, and found no significant differences in the rate of anomalies. Sufficient questions are raised by these studies to indicate that medroxyprogesterone acetate, norethindrone, and norethindrone acetate should not be used during pregnancy. The luteolytic potential of these agents also makes them undesirable for use in the treatment ofluteal phase defects. There is no consensus that valid evidence exists to indicate that progesterone and 17-hydroxyprogesterone are teratogenic, nor is there any physiologic reason to expect them to be, since they
507
are physiologic and are used in physiologic doses. Because of the action ofthe Food and Drug Administration, however, these reports should be discussed with the patient, as well as the package insert which is given to her. This information may be supplemented and balanced by referring her to the article "Proceedings of the Symposium 'Progesterone, Progestins, and Fetal Development'" by Chez. 57 In summary, the concluding remarks by Chez57 are pertinent: "The question must be raised about the cost to patients who are denied treatment-costs in terms of their general quality oflife. Since there is statistically significant evidence that the administration of exogenous progesterone can diminish the incidence of premature labor, can diminish one cause of infertility, and can diminish one cause of spontaneous abortion, there are critical public health issues. The patient's ethics and priorities and the physician's response to these priorities constitute elements of the art of medicine." From the evidence available, the benefits of properly prescribed progesterone therapy for the proper diagnosis appear to outweigh the risks. Luteal phase defects can be considered a deficiency state, leading to infertility. Substitutional therapy with progesterone, endogenous or exogenous, has proved its effectiveness. Judicious use of progesterone in documented cases is an appropriate approach to luteal phase defects.
REFERENCES 1. Jones GS: The luteal phase defect. Fertil Steril 27:351,
1976 2. Jones GS, Delfs E: Endocrine patterns in term pregnancies following abortion. JAMA 146:1212, 1951 3. Jones GS, Madrigal-Castro V: Hormonal findings in association with abnormal corpus luteum function in the human: the luteal phase defect. Fertil Steril 21:1, 1970 4. Jones GS, Moraes-Ruehsen MD, Johanson AJ, Raita S, Blizzard RM: Elucidation of normal ovarian physiology by exogenous gonadotropin stimulation following steroid pituitary suppression. Fertil Steril 20:1, 1969 5. Strott CA, Cargille CM, Ross GT, Lipsett MB: The short luteal phase. J Clin Endocrinol Metab 30:246, 1970 6. Vande WieleRL, Bogumil J, Dyrenfurth I, Ferin M, Jewelewicz R, Warren M, Rizkallah J, Mikhail G: Mechanisms regulating the menstrual cycle in women. Recent Prog Horm Res 26:63, 1970 7. Jones GS: Luteal phase defects. In Progress in Infertility, Second Edition, Edited by SJ Behrman, RW Kistner. Boston, Little, Brown and Co, 1975, p 299 8. Wenner R: Les antiprolactines. Actual Gynecol
