Can you develop luteal phase defect

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What causes a short luteal phase? Symptoms of a short luteal phase. Diagnosing short luteal phase. Treatment for short luteal phase. Controversies about luteal phase defect. Next steps. Parenthood Pregnancy. Read this next. Get the app iPhone. Learn More. Your cart is empty. What is the luteal phase? What is a luteal phase defect?

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Although small, this investigation highlights the ability of follicular-phase intervention to improve the luteal phase environment, although the exact therapeutic mechanism is unclear. In general, because exogenous gonadotropins offer more potent stimuli to the ovaries than CC, they are more likely to overcompensate for the underlying defect.

For this reason and cost and risk issues, CC is the first-line ovulation induction treatment, using the lowest effective dose that normalizes luteal parameters. A typical CC regimen would be 50 mg daily for 5 days beginning on cycle days 3 to 5.

In LPD cases in which mild hypothalamic dysfunction is suspected, such as in women who are less than their ideal body weight, doses of 25 mg daily taken for 5 to 10 days may be more efficacious, avoiding undesirable effects of CC therapy, such as diminished cervical mucus quality.

Because normal values for luteal progesterone in CC cycles have never been unequivocally established, TEB is the mainstay for evaluation of therapy.

Exogenous progesterone supplementation of the luteal phase is the most common treatment of LPD. Although early reports of the use of synthetic progestins showed no associated teratogenicity with first-trimester exposure, supplementation has been limited almost exclusively to natural progesterone preparations, not synthetic progestins.

This is due in part to evidence that the latter suppress endogenous progesterone secretion after ovulation. Results of hormone replacement cycles in women scheduled to receive embryos from donor oocytes provide excellent insight into the absolute needs for proper nidation. These women are typically menopausal or in a state of pseudomenopause brought about by the use of GnRH analogues, such as leuprolide acetate.

What is immediately clear from such experiments is that replacement of progesterone after first priming the endometrium with estrogen is enough to allow and sustain pregnancy, despite omission of other luteal phase products. A summary of such studies Table 2 shows the superiority of intramuscular progesterone and vaginal preparations as opposed to oral micronized progesterone.

Still, an understanding of the pros and cons of each form of therapy may influence decisions depending on the clinical scenario.

TABLE 2. P, progesterone; MP, micronized progesterone; p. Adapted from Tavaniotou A, Smitz J, Bourgain C, Devroey P: Comparison between different routes of progesterone administration as luteal phase support in infertility treatments. Hum Reprod Update , Oral micronized progesterone offers the most convenient form of luteal supplementation; however, its use may be associated with systemic side effects, such as sedation, flushing, and nausea.

After ingestion, progesterone is absorbed rapidly and metabolized by the intestines, later reaching the liver where glucuronyl and sulfuryl transferases render it hydrophilic and more easily excreted. A single mg dose can be expected to cause a C max in serum of 6. Controversy exists regarding the true progesterone effect on the endometrium at a given serum concentration after oral micronized progesterone ingestion because some investigators have shown assay interference from high concentrations of progesterone metabolites.

Vaginal progesterone delivery offers several advantages over oral progesterone, most notably, avoidance of first-pass metabolism in the gastrointestinal tract and liver with a lower incidence of sedation. Patients may experience side effects, such as a discharge, irritation, or local feelings of warmth, but generally find them to be acceptable.

The main disadvantages of suppositories are the lack of standardized commercial preparations and the undesirable discharge they can create for the patient. In one of the only prospective, randomized studies comparing oral and vaginal progesterone in non-IVF, CC ovulation induction cycles, vaginal progesterone cycles were marked by lower pregnancy rates and higher insulin-like growth factor binding protein-1 IGFBP-1 serum concentrations.

As an alternative, a newer intravaginal formulation of natural progesterone in a water-soluble, polycarbophil gel that adheres to the vaginal mucosa may be used, causing considerably less discharge with equal or better tissue levels in the endometrium. The exact dose of progesterone gel for the most effective treatment of LPD has yet to be determined; however, commercially available preparations of 45 and 90 mg are available in North America.

Another method of supplementation is daily intramuscular injection of Although this method is the most uncomfortable option for patients, a single mg injection provides luteal phase serum levels of progesterone, with measurable elevations 36 hours later.

In addition to the use of progesterone for supplementation, some clinicians have chosen to administer hCG intramuscularly. Exogenous hCG, because of its structural homology with LH, stimulates the corpus luteum to increase steroid hormone production. Various doses and dosing intervals have been used in assisted reproductive cycles, most commonly to U every 3 days after ovulation. Its use in LPD cycles is limited. The disadvantages of this technique include the need for repeated injections and the inability to detect early pregnancy reliably with serum hCG levels.

In addition, in cases of LPD in which a small cell defect predominates, hCG may have little or no impact on luteal function. Experience with ovulation induction in which GnRH agonists were used for down-regulation has shown an increased risk of ovarian hyperstimulation syndrome with hCG luteal support.

Therapies for LPD specifically targeted to the central nervous system have shown promise in the research setting. The ability to induce normal ovulatory menstrual cycles in women with hypothalamic amenorrhea using a GnRH pump led investigators to apply this treatment to women with LPD.

One patient conceived during 1 of the 12 treatment cycles; all others experienced improvement in endocrine or histologic parameters. The use of this therapy clinically is limited because of cost, invasiveness, and the capability of achieving comparable pregnancy rates using CC or gonadotropins. Other investigators have shown resolution of LPD and increased fecundity with treatment with nonhormonal drugs that act on the central nervous system, such as diphenylhydantoin and nialamide.

Bromocriptine is a dopamine agonist with central nervous system activity used to inhibit secretion of prolactin from the anterior pituitary.

In theory, it may be useful in lowering the subtle elevations in prolactin that are difficult to detect with random serum measurements and that may contribute to the development of LPD. In practice, bromocriptine should be prescribed 1. Several uncontrolled studies that report pregnancy rates after treatment of LPD describe acceptable fecundity rates compared with a fertile population and offer compelling evidence for therapy. Their patients initially were treated with progesterone vaginal suppositories 25 mg twice daily with repeat TEB performed in the first treatment cycle to judge efficacy.

Women continued on this regimen for six cycles regardless of TEB findings. Women who failed to conceive were switched to CC 50 mg daily on cycle days 5 to 9, again with TEB, and this regimen was continued for 6 months regardless of TEB findings. Women who failed were treated with CC with progesterone, gonadotropins, or dexamethasone if appropriate.

Using life-tablele analysis, they showed normalization of cycle fecundity and cumulative pregnancy rates when TEB was corrected. Although fecundity for patients treated with progesterone was higher than for those treated with CC, a significant negative selection bias against CC existed because only patients who failed progesterone treatment were included in this treatment group.

Cumulative pregnancy rate with luteal phase deficiency treatment. The cumulative pregnancy rates over nine cycles from the study of Daly and associates are shown here. A significant improvement in the cycle fecundity rate with treatment of luteal phase deficiency is noted; it was indistinguishable from the cycle fecundity of a normal fertile population.

Solid evidence for the effect of treatment for LPD also came from a study by Murray and coworkers, who used vaginal progesterone or CC for their patients. Patients were continued on one type of therapy if TEB was corrected. Overall mean follow-up time for both groups was 6 months. No significant difference was detected between the two treatment groups.

In both studies, cumulative pregnancy rates for patients with corrected LPD were similar to rates projected for a normal, fertile population, supporting treatment of LPD. Luteal phase deficiency cumulative pregnancy rate. In the study by Murray and colleagues, patients with luteal phase deficiency achieved an improved cycle fecundity rate with either A progesterone P or B clomiphene citrate CC supplementation treatment. The cumulative pregnancy rate achieved with each treatment did not equal the pregnancy rate of a normal group.

For the subgroup of LPD patients who suffer from recurrent miscarriage, several reports present successful series of patients treated with progesterone or CC. A retrospective review by Tho and associates of couples who presented with recurrent miscarriage at their institution identified 23 couples for whom abnormal TEB LPD was the sole abnormality.

Twenty-two couples were treated with luteal phase progesterone supplementation; the remaining couples were treated with CC and progesterone. An extensive meta-analysis of controlled trials of progesterone support for pregnancy in women with recurrent miscarriage by Daya identified three studies in the literature that were random or quasi-random with placebo controls. Although none of these studies specifically diagnosed LPD before instituting progesterone therapy, the recognized incidence of LPD in this group By combining these three studies, Daya found an overall odds ratio for treatment of 3.

Taken together, the prevailing evidence suggests that treatment can correct inadequate corpus luteum function despite the lack of well-designed studies. At present, selection of a particular treatment modality in our center depends on the presumed cause of LPD. Most obvious are women with hyperprolactinemia or abnormal thyroid function; they should be treated appropriately to correct these disorders, which also adequately treats LPD in most instances.

CC rarely is used as a first-line treatment because of its potential to induce LPD, but it is the treatment of choice for women with abnormally short or long follicular phase length and for women who have sonographic documentation of ovulation from follicles of less than 20 mm mean diameter. In these instances, the cause of LPD seems to be inadequate folliculogenesis, which is generally more refractory to progesterone supplementation.

In most of our patients, administration of natural progesterone in the luteal phase has been the first line of therapy. We use oral micronized progesterone, mg three times daily, beginning 4 days after the detection of a preovulatory urine LH surge or an ovulation-triggering injection of hCG.

For patients who experience side effects related to oral progesterone, we administer mg of micronized progesterone vaginally twice daily. The less frequent dosing interval is possible because of prolonged tissue levels using this route of delivery. Because the survival of the blastocyst depends on adequate implantation in the secretory endometrium, intuitively the time to begin treatment is early in the luteal phase several days after ovulation.

Withholding treatment until documentation of pregnancy 2 to 3 weeks after ovulation does not have the same beneficial effects on nidation, although adequate trials comparing early with late onset of treatment are lacking. In our institution, we begin progesterone supplementation 3 to 4 days after the presumed day of ovulation to avoid suppressing periovulatory cervical mucus and to maximize the effect of progesterone on the endometrium before implantation.

This translates into starting treatment 4 days after a positive urine test for LH or an artificial surge using exogenous administration of hCG to 10, U during monitored cycles.

If no pregnancy results in a particular treatment cycle, progesterone supplementation is discontinued with the onset of menses, with reinstitution in the luteal phase of the next cycle.

The duration of treatment should be at least three but not more than six cycles without a re-evaluation of the patient. This recommendation is based on studies of luteectomy in early pregnancy in women scheduled to undergo therapeutic abortion. Exogenous progesterone delivered after lutectomy at 7 weeks preserved pregnancies. If women taking oral micronized progesterone begin to develop worsening nausea and bloating that makes their capsules less palatable, they may convert to twice-daily vaginal capsules or suppositories as alternatives.

Because the use of CC, gonadotropins, or exogenous progesterone alters the pharmacodynamics of circulating progesterone, assessment of treatment should be performed using an endometrial biopsy. After treatment, if the biopsy specimen remains out-of-phase, an alternative treatment or, in the case of CC, a higher dose should be used.

With the potential for induced LPD with CC or gonadotropins, concomitant use of progesterone may be necessary. The decision to treat or not to treat a patient is at the core of what it means to be a physician. When performing diagnostic tests and developing treatments, one always must keep in mind the principles of beneficence and nonmalfeasance—that is, whether treatment helps or harms the patient.

This issue is best broached by using the technique of receiver operator characteristic ROC curves. The resulting curve bends toward the upper left corner of the graph, with an initial slope near infinity close to the y-axis and a later slope close to 0 away from the y-axis. The other factor is the pretest probability p , the chance that the patient has the disease before any testing begins. The optimal cutoff point for normalcy varies from patient to patient based on these parameters see Fig. With a disease such as cancer, in which the potential net benefit of treatment is great but the cost of erroneously treating is as great or greater, one would like to have a cutoff point on the curve where the slope is steep i.

The opposite is true in the case of LPD: The potential benefit of treatment with progesterone i. Our threshold value for making the diagnosis of LPD should be set to allow a relatively high percentage of false-positive results based on the estimates used in this scenario.

For some patients and some forms of treatment, these ratios and pretest probabilities are not applicable. Several excellent reviews on the ROC concept are available. Although some would argue against testing in favor of empirical therapy, the latter is discouraged because no treatment is without some detrimental effect.

A theoretical receiver operating characteristic curve for selected cutoff levels of pooled progesterone. LPD is a subtle disorder of corpus luteum function and has a multifactorial cause Fig. Current evidence in the medical literature confirms its existence, but investigations to date have failed to characterize its true incidence conclusively.

The diagnosis is best made by measuring serum progesterone levels daily throughout the luteal phase. This method is impractical, however, except in a research setting. The best means of estimating luteal phase function available to clinicians is three pooled mid luteal progesterone levels.

Although TEB has enjoyed widespread use in past investigations of LPD, it is a suboptimal diagnostic standard that still plays an important role as a test of adequacy during treatment cycles. Despite the lack of randomized, controlled trials proving efficacy of treatment, compelling reports point to improved pregnancy rates when treatment results in normalization of TEB.

In consideration of the cost-benefit equation as applied to LPD, clinicians are urged to seek out this disorder and appropriately treat it when it is present. Luteal phase deficiency diagnosis and treatment flow chart. For most patients, the initial diagnosis of decreased progesterone secretion should be confirmed before treatment. When treatment is initiated, it should be verified that the treatment has corrected the defect.

Treatment should be continued for six cycles for maximal efficacy. Endocr J , Int J Fertil , Li T, Dockery P, Cooke I: Endometrial development in the luteal phase of women with various types of infertility: Comparison with women of normal fertility.

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