In the post on the workup of the ovulatory factor, the difficulty in the diagnosis of the disturbed luteal phase was emphasized. Not only do multiple physiologic disorders probably cause the upset, but often the upset apparently comes and goes, occurring during one cycle but not another. These create difficulties in diagnosis, make rational therapy problematic, and, in particular, its evaluation almost impossible. Nevertheless, the luteal phase deficiency factor in infertility has been recognized for many years, and a number of treatment programs have been recommended.
Before resorting to direct treatment of the deficient corpus luteum, or the endometrium, the physician should make every effort to cure any underlying general disorder if it is the cause of this relative ovulatory defect.
Polycystic ovarian disease, or milder forms of adrenal androgenic hyperplasia, is usually accompanied by anovulation or amenorrhea, because of the inhibiting action of excess androgens at the hypothalamic or pituitary level. Occasionally the inhibitory effect is incomplete; ovulation occurs, but there is sufficient inhibition to affect the quality of corpus luteum function. Thyroid deficiency, nutritional deficiency, and emotional tension are other causes of luteal phase deficiency that are amenable to treatment. Hyperprolactinemia is another cause of luteal phase deficiency, and it responds well to Parlodel® 2.5 to 5.0 mg daily.
If no specific causes are found, as in most cases, the two present treatments of choice are clomiphene citrate and progesterone. It is impossible to say which of these two methods is superior. No parallel series have been reported; probably the previously mentioned inconsistencies in diagnosis make such a study impossible.
Clomiphene citrate stimulates ovulation by allowing the release of gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The logical reason for using clomiphene in the treatment of luteal phase deficiency is based on those studies demonstrating a deficiency of FSH in the follicular phase of the cycle in cycles with short luteal phases (). It has been postulated that the low levels of FSH in the first part of the cycle result in an inadequate follicle that ovulates but becomes a poor corpus luteum with deficient progesterone production. Treatment with clomiphene increases FSH, which improves folliculogenesis. This results in a more normal corpus luteum with more suitable progesterone production. However, the majority of cycles in which treatment has been carried out are not significantly shortened. The diagnosis is usually made by a combination of poor basal body temperature chart, lowered progesterone levels, or an endometrium that is out of phase. On the contrary, cycles such as these are often found to have a relatively low LH surge at midcycle following normal FSH stimulation. Still others show a lowered tonic release of LH during the luteal phase.
The definitive work of Downs and Gibson demonstrated that clomiphene was only effective when the endometrial biopsy was 5 days or more out of phase, the situation more frequently found with short luteal phase (). Milder degrees of luteal phase deficiency did not respond as well to clomiphene therapy.
Thus, in selecting clomiphene therapy, the therapist should be aware of the variability of the pathophysiology, the length of the luteal phase, as well as the mechanism of action of the different medications involved and, with this in mind, should select clomiphene as the optimal therapy only in the short luteal phase. Poor results — and a pessimistic attitude toward all clomiphene citrate therapy — are more likely if clomiphene is used for all types of luteal phase defects. There are few studies available that have really evaluated its efficacy. One study in which eight patients with short luteal phase were treated with clomiphene, seven pregnancies occurred. In another where no attention was paid to the luteal phase, the success rate with clomiphene was only 21%. Furthermore, as in all therapy with clomiphene, the therapist must be alert to its adverse effects on the cervical mucus, and if this occurs, treat the condition with small doses of estrogen or even intrauterine insemination.
In luteal phase deficiency, there is a degree of progestational endometrial effect, but the endometrium is not sufficiently stimulated. Here, the condition is obviously associated with a progesterone deficiency.
Jones was one of the earliest to prescribe progesterone for luteal phase deficiency. In an excellent review of the subject, she outlined the pathophysiology in treatment of this condition. She believes strongly that progesterone, itself, should be administered, since synthetic progestins have been shown to suppress corpus luteum function. Therefore, she recommends the use of progesterone vaginal or rectal suppositories, 25 mg, twice daily, starting 2 or 3 days after the basal body temperature rise.
My preference is to start with one suppository daily beginning 2 or 3 days after the rise in basal body temperature. An endometrial biopsy is performed 2 or 3 months later to see if additional progesterone is needed.
Once pregnancy has been established and diagnosed, it is advantageous to continue exogenous steroids for 3 or 4 months. Studies in the early 1970s raised the possibility of increased incidence of congenital heart problems in the offspring of mothers given progestational steroids in early pregnancy. The Food and Drug Administration recommended discontinuing the use of routine progesterone treatment in early pregnancy. Luteal phase deficiency, however, is a condition in which there is a definite indication for progesterone therapy. In the early 1970s and early 1980s the couple was made aware of the supposed risks, and the pros and cons had to be carefully weighed. Recently, however, the statistical significance of the original papers have been questioned. A number of studies have shown no evidence of increased abnormalities as a result of progesterone therapy in early pregnancies.
Results of Progesterone Therapy
Because of spontaneous remissions previously described, it is difficult to have scientifically controlled studies. However, there are more reports concerning progesterone therapy than clomiphene therapy. One of the first series was reported by Jones in 1962, where 21 of 555 patients with primary infertility were diagnosed as having luteal phase defect. Of 15 treated with progesterone, 12 conceived. The results of four more recent reports of progesterone therapy in luteal phase deficiency are shown in Table Progesterone Suppositories In the Treatment of Luteal Phase Deficiency. The pregnancy rates ranged from 41% to 69% with an overall rate of 46% after up to 6 months of therapy. Of 1000 fertility patients seen in my office over a 6-year period, 62 were diagnosed as having had a luteal phase deficiency. Progestational therapy resulted in a 60% pregnancy rate. Clomiphene citrate given in 20 cases resulted in a pregnancy rate of only 30%.
Table Progesterone Suppositories In the Treatment of Luteal Phase Deficiency
|Study||Year||Number of patients||Pregnancies||Percent|
|Garcia et al.||1977||14||6||43|
|Soules et al.||1977||17||7||41|
|Wentz et al.||1984||54||23||43|
|Rosenberg et al.||1980||13||9||69|
When both clomiphene and progesterone treatment fail, one can then consider the use of gonadotropins. Human chorionic gonadotropin can be used in a dose of 2000 to 4000IU every other day, starting 2 or 3 days after the basal body temperature rise. This form of treatment is expensive and inconvenient because it requires injections every other day. This treatment can delay menses. Since there is no way to diagnose pregnancy because the chorionic gonadotropin will interfere with the pregnancy test, one must arbitrarily stop the treatment to see whether menses will occur; thus the advantages of sustained stimulation of the corpus luteum are lost. No significant studies of its efficacy are available. Postmenopausal gonadotropin (Pergonal) may play a role in the treatment of the short luteal phase, but here too, the treatment is expensive and inconvenient. Postmenopausal gonadotropin has the added problem of hyper-stimulation with ovarian enlargement and multiple pregnancies. Thus far, only preliminary reports have been published. One study described the use of pituitary FSH for luteal phase deficiency — 5 of 15 women conceived. The patients were not given progesterone beforehand, so theoretically a better percentage could have been obtained with the much simpler medication. In addition, pituitary FSH is no longer available for even investigative use.
Selections from the book: “Infertility: A Clinician’s Guide to Diagnosis and Treatment”. Edited by Melvin L. Taymor, M.D., 1990.