Diagnosis and treatment of luteal phase deficiency: a committee opinion

PHYSIOLOGY OF NORMAL LUTEAL FUNCTION

In medically unassisted cycles, progesterone secreted by the corpus luteum is essential for the establishment and maintenance of pregnancy until the placenta becomes competent to secrete sufficient progesterone. An example of this necessity is that removal of the corpus luteum before the development of adequate placental function results in spontaneous pregnancy loss (1). Considering normal luteal phase physiology, the following observations have been made:

• A typical luteal phase length is relatively fixed at 12–14 days but may range from 11-17 days.
• Progesterone levels peak in non-pregnancy cycles 6–8 days after ovulation.
• Progesterone production by the corpus luteum is pulsatile, secreted in response to luteinizing hormone (LH) pulses; progesterone pulses are more pronounced in the mid- to late-luteal phase; and progesterone levels may fluctuate up to 8-fold within 90 minutes (2).
• The endometrial response is a reflection of follicular-phase estrogen and luteal-phase estrogen and progesterone. In turn, the production and secretion of these hormones is dependent upon follicular phaselicle development, ovulation, and luteal phase corpus luteum function.
• Once implantation occurs, progesterone secretion by the corpus luteum depends on rising human chorionic gonadotropin (hCG) levels.
• Failure of hCG levels to increase results directly in corpus luteum failure and a decline in progesterone levels (3).
  
  

DEFINITION OF LUTEAL PHASE DEFICIENCY (LPD)

Luteal phase deficiency (LPD) was first described in 1949 (4) and broadly refers to an abnormal luteal phase. Given the importance of the luteal phase in the establishment of a normal pregnancy, a defect in luteal phase (i.e., LPD) has been suggested as a cause of pregnancy loss, and most notably, recurrent pregnancy loss. Classically, clinically detected LPD refers to a luteal phase of ≤10 days in length, but alternate definitions include ≤11 and ≤9 days. Alternative biochemical definitions also have been proposed, e.g., a low integrated progesterone level across the luteal phase. Clinical and biochemical tests have been proposed to diagnose LPD (see below).

 

POTENTIAL CLINICAL IMPLICATIONS OF LPD

Since ovarian progesterone is required for a normal intrauterine pregnancy, the potential for ovarian inadequacy to cause infertility or pregnancy failure is clearly plausible. Despite the wide fluctuations observed in circulating progesterone levels during the luteal phase, some investigators have found a more rapid rise of progesterone and higher mid-luteal estrogen and progesterone levels in cycles resulting in conception compared with cycles in which conception does not occur (5), though early effects of the embryonic hCG during a conception cycle cannot be ruled out completely. Alternatively, other studies demonstrate that luteal phase profiles are similar within the same woman in cycles that resulted in successful pregnancy vs. cycles that resulted in early pregnancy loss (6, 7).

Luteal phase deficiency also purportedly has been associated with infertility and subfertility (8–10), first-trimester pregnancy loss (11), short menstrual cycles (12–15), and premenstrual spotting (16). Importantly, LPD also has been diagnosed in random cycles of normally menstruating women (14). Overall, it is unclear if abnormal luteal function is an independent cause of implantation failure or early pregnancy loss in natural cycles.

PATHOPHYSIOLOGY BASIS FOR LPD

The pathophysiology of LPD may include several mechanisms that ultimately affect endometrial development. Firstly, LPD has been described as a condition in which ovarian hormone production is not of a sufficient quantity or temporal duration to maintain a functional secretory endometrium and allow normal embryo implantation and growth. A short luteal phase has been associated with low follicular phase follicle stimulating hormone (FSH) levels, low follicular phase estradiol levels, altered follicular phase FSH/luteinizng hormone (LH) ratios, and abnormal FSH and LH pulsatility (17). These follicular-phase abnormalities have been associated with subsequent reductions in luteal phase estrogen and progesterone levels (14, 15, 18–20).

Alternatively, it is possible that LPD may develop as a result of inadequate endometrial response to adequate hormone levels. For example, it has been proposed that some patients demonstrate an endometrium that has an altered (deficient) response to progesterone that reduces fertility (21–24). With such progesterone resistance, it is the endometrial response to the steroid rather than the amount or duration of progesterone exposure that is defective.

Idiopathic LPD implies an abnormality of the luteal phase in the absence of an identifiable disease process. Given the requirement of progesterone for normal pregnancy, it would be assumed that there should be a threshold serum progesterone concentration necessary for the establishment and maintenance of pregnancy. However, because of the pulsatile nature of serum progesterone, it has not been possible to define a normal threshold peak, trough, or average concentration for progesterone in natural cycles. Modeled cycles, following the administration of exogenous estradiol and progesterone, have suggested that threshold serum progesterone levels for a normal endometrial histology may be as low as 2.5 ng/mL, but that normal gene expression may require a peak threshold between 8–18 ng/mL (25).Idiopathic LPD has not been proven to cause infertility (8, 26).

CONDITIONS THAT ALTER THE LUTEAL PHASE

Pathologic conditions that disrupt normal gonadotropin releasing hormone (GnRH) and LH pulsatility can hypothetically lead to LPD. Examples of conditions that have been associated with LPD include hypothalamic amenorrhea (27–31), eating disorders (32), excessive exercise (27), significant weight loss (33), stress (34, 35), obesity (36), polyendocrine metabolic ovarian syndrome previously known as polycystic ovary syndrome (35), endometriosis (37), aging (38), undiagnosed or inadequately treated 21-hydroxylase deficiency (39), thyroid dysfunction (40), hyperprolactinemia (40), ovarian stimulation alone (41), and assisted reproductive technology use (42). These studies vary in how LPD was defined and are limited by the challenges already described in diagnosing LPD.

Women with hyperprolactinemia had shortened luteal phases with lower plasma progesterone compared with those with  normoprolactinemic cycles (43). Thyroid and prolactin disorders may disrupt GnRH secretion and alter the hypothalamic-pituitary-ovarian axis. The increased secretion of thyrotropin-releasing hormone in hypothyroidism may result in hyperprolactinemia by stimulating lactotroph prolactin production (44, 45).

Additional conditions that have been associated with altered luteal progesterone levels include renal transplantation (46), increased beta-endorphin levels (47), and lactation (48). Obesity has been associated with a reduction in fertility and increased pregnancy loss rate (49). This negative impact is evident particularly in the setting of morbid obesity. A study evaluated LH pulsatility and urinary progesterone metabolites in women with obesity compared with normal- weight control subjects (50). As with women with anorexia, an alteration in LH pulsatility (a reduction in LH pulse amplitude) and a reduction in luteal-phase pregnanediol glucuronide (the major metabolite of progesterone) excretion was observed in women with obesity. Whether this abnormality, possibly via LPD, contributes to the lowered fecundity rates in obesity is unknown.

Advanced reproductive age also has been associated with abnormalities in luteal phase function. Studies have demonstrated decreased progesterone production and deficiencies in luteal phase progesterone and estradiol metabolites in women of late reproductive age (51, 52). Whether these abnormalities contribute to the lower pregnancy rates and higher pregnancy loss rates associated with aging is unclear. Interestingly, isolated diminished ovarian reserve has not been associated with LPD, following adjustment for age (53).

Because conditions that alter normal gonadotropin secretion impair follicular development and ultimately corpus luteum function, resultant changes in the amount and duration of luteal sex steroid secretion may compromise endometrial development. Presumably, correcting these underlying conditions would correct the abnormal luteal estrogen and progesterone secretion. Given this controversy, an evaluation for underlying causes of a possible LPD could be initiated following shared decision making.

PROPOSED DIAGNOSTIC TESTS FOR LPD

The diagnosis of LPD is made clinically. Multiple diagnostic tests have been proposed, including clinical, biochemical, and histological tests, but none has been able to differentiate reliably between fertile and infertile women (54–57). In order of increasing invasiveness, the different methods proposed for diagnosing LPD include a shortened luteal phase on the basis of menstrual cycle length, a shortened luteal phase on the basis of basal body temperature charting or urinary LH surge detection kits, the measurement of a single or multiple serum progesterone levels, and an endometrial biopsy.

Menstrual cycle length

Monitoring of basal body temperature or urinary LH surge detection and monitoring of luteal length may substantiate normal ovulation and adequate luteal length. The average luteal phase length is 14 days, with a normal variation of 11–17 days (14, 58, 59). A short luteal phase has been described as an interval of less than 9-11 days from the LH peak to the onset of menstrual flow (14, 17, 58). However, there are multiple definitions in the literature of how many days constitute LPD, which makes an evidence-based diagnosis difficult.

Short luteal phases also have been diagnosed in noninfertile women with regular menstrual cycles. One study demonstrated that 13% of ovulatory menstrual cycles were associated with a luteal length <10 days (17). Another study demonstrated that 18% of menstrual cycles had a luteal phase length <12 days (60). Although women with a shortened luteal phase in this latter study were less likely to conceive in the subsequent month, their overall fecundity at 12 months was not lower.

Given the above limitations of describing the short luteal phase, it may be reasonable to consider LPD when clinically indicated in the presence of a luteal phase of <10 days. However, the aforementioned findings also suggest that a shortened luteal phase length is relatively common and not associated with decreased fecundity over 12 months. Assessing an adequate luteal phase is complicated further by the fact that the luteal phase length cannot be measured in cycles that result in pregnancy, but only in cycles that do not result in pregnancy.

Progesterone levels

While luteal serum progesterone levels are used commonly to assess luteal function in the absence of pregnancy, progesterone levels typically peak 6–8 days after ovulation (3). A luteal progesterone value of >3 ng/mL is presumptive and sufficient evidence of recent ovulation (61). Therefore, random serum progesterone levels can be used to establish that ovulation occurred in a menstrual cycle; however, no minimum serum progesterone concentration defines normal or fertile luteal function.

Progesterone is secreted in pulses in response to LH pulses, with progesterone values oscillating between 5 ng/ mL and 40 ng/mL over short periods of times in normally ovulatory women, making a single random measurement difficult to interpret (2). In ovulatory cycles, luteal progesterone values of <5 ng/mL occur 8.4% of the time and values of <10 ng/mL occur 31.3% of the time (17). Furthermore, corpus luteum function varies from cycle to cycle in normal fertile women. Therefore, there are substantial limitations to diagnosing LPD using a single progesterone level.

Some studies have suggested that the best marker of luteal phase progesterone production is obtained by measuring serum progesterone daily during the luteal phase and adding the values to produce an integrated luteal progesterone value. An integrated luteal phase progesterone value of <80 ng/mL represents the bottom 10th percentile of cycles and has been proposed as a diagnostic test for LPD (54). Given the impracticality of daily serum testing, three daily luteal progesterone values, obtained between luteal phase days 5–9, totaling <30 ng/mL also has been proposed as an alternate diagnostic criterion for LPD. While pooled luteal-progesterone values may better reflect overall luteal phase progesterone production, this test has not been clinically validated and may be impractical clinically.

Combined menstrual cycle length and mid-luteal progesterone testing

In the BioCycle Study, 8.9% of cycles in normally menstruating women had a luteal phase of <10 days, which the investigators defined as ‘clinical’ LPD (17). Similarly, 8.4% of women had a mid-luteal serum progesterone measurement of <5 ng/mL, which the investigators defined as ‘biochemical’ LPD. Clinical and biochemical LPD were associated with lower follicular estradiol, lower luteal estradiol, lower luteal progesterone, and lighter menstrual flow. Almost all of the women with a clinical LPD of <10 days also had a mid-luteal serum progesterone value <10 ng/mL. Therefore, the investigators proposed using the combination of these two thresholds to define LPD, which when defined as such had a prevalence of 8.2% in their study (17). While combined testing has not been validated further, this method may provide a tool for future clinical research assessment of LPD.

Endometrial biopsy

Abnormalities of endometrial maturation have been viewed historically as the gold standard to diagnose LPD (62, 63). In theory, whether the maturation of the endometrium is delayed by inadequate ovarian hormone secretion or is delayed because of an intrinsic endometrial abnormality, the resulting defect is thought to prevent normal implantation or early placental development (63). Studies that have defined the diagnostic criteria for LPD using the endometrial biopsy have relied on the traditional microscopic appearance of luteal phase endometrial development to determine whether ‘‘in-phase’’ (normal) or ’’out of phase’’ (abnormal) (62). However, implantation is associated with changes in a number of factors beyond endometrial histology, including steroid receptors, structural proteins, growth factors, cytokines, receptors, and pinopodes (64–69). Additionally, maturation may differ across various sections of the endometrium and a single endometrial biopsy may not be able to assess global endometrial development. Defining clinically applicable criteria for normal luteal phase endometrial development is complex and evolving.

Prospective, blinded, clinical trials demonstrate that the endometrial biopsy is an imprecise tool for differentiating fertile women from infertile women. In two randomized trials of healthy, regularly menstruating, fertile women, histologic assessment of endometrial maturation was delayed in up to 25% of biopsy cycles. Furthermore, the variability within individuals from one cycle to the next was high and there also was high variability in histologic dating as assessed by different reviewers (55, 56). In a multicenter randomized clinical trial (RCT) of 847 women with regular menstrual cycles, 49% of mid-luteal and 35% of late-luteal biopsies were ‘‘out of phase,’’ and there was no difference when comparing fertile and infertile women (57). Together, these reports confirm that the endometrial biopsy for histologic endometrial dating is not a valid clinical diagnostic tool for the identification of an infertile population or for the diagnosis of LPD.

Consistent with these findings are studies designed to test the hypothesis that low progesterone levels lead to inadequate endometrial development (25, 70). In these studies, multiple doses of intramuscular progesterone were given on the background of supplemental estradiol following suppression of ovarian function with a GnRH agonist. The exogenous hormone cycles were compared with natural cycles and each other. Normal endometrial histology was seen with peak serum levels as low as 2.5 ng/mL, but completely normal gene expression required a peak threshold above 8 to 18 ng/mL (25).

Other endometrial markers

Because the histologic evaluation of the endometrium is imprecise, many additional biochemical, morphologic, and molecular markers of endometrial function have been proposed to assess endometrial receptivity to implantation (63, 69). However, no marker of endometrial receptivity in a natural cycle has been validated in a RCT or demonstrated the ability to distinguish normal fertile from infertile women. At this time, molecular markers of receptivity remain experimental and are not considered valid clinical diagnostic tools.

In summary, currently there is no reproducible and clinically practical standard to diagnose LPD and distinguish fertile from infertile women. The roles of luteal phase progesterone levels, endometrial biopsy, and other diagnostic studies have not been fully established, and performance of these tests cannot be recommended. Furthermore, given the lack of a clear correlation between LPD by alternative definitions and clinically relevant outcomes, there is no test that can be considered the gold standard.

PROPOSED TREATMENTS

Given the lack of a clear diagnostic criteria for LPD and the overlapping results in most tests between fertile and infertile women, it is not surprising that quality data are lacking for the treatment of LPD. The first approach to treatment of potential LPD is the correction of any underlying condition, such as hypothalamic or thyroid dysfunction, or hyperprolactinemia. If no underlying abnormality is identified, then treatment becomes empiric and generally is not recommended. This should be interpreted in the context that LPD is difficult to define and there has been scant quality literature investigating treatment for LPD. The aim of empiric treatment historically has been to improve ovulatory function, promote endometrial maturation, enhance endometrial receptivity, and support implantation and development of an early pregnancy. Empiric strategies have included supplemental luteal progesterone, luteal progesterone plus estrogen, luteal hCG, or ovarian stimulation with clomiphene or gonadotropins.

Ovarian stimulation

The use of agents to stimulate the ovaries may improve the fertility of subfertile women. The biologic plausibility of this treatment strategy is based on the physiologic continuity between the developing follicle and the corpus luteum. Improved preovulatory follicular dynamics should improve corpus luteum function. However, attempts to link poor fertility outcomes to these surrogate endpoints have been unsuccessful and ovulation induction has not been demonstrated to treat LPD (71–74).

Progesterone

Progesterone can be administered via oral, vaginal, subcutaneous, and intramuscular routes. The use of progesterone following fertility treatments is distinctly different than using it to supplement the natural menstrual cycle. While progesterone is beneficial following various therapeutic infertility treatments, there is no evidence that progesterone is beneficial for fertility in natural cycles. Similarly, there is no evidence that progesterone is beneficial for the treatment of LPD.

There are no RCTs investigating progesterone supplementation for women with LPD. Studies have investigated progesterone supplementation for recurrent pregnancy loss, which theoretically may overlap with LPD because of inadequate progesterone support for the early pregnancy (75). A large multicenter, double-blind, placebo-controlled trial randomized 836 women with a history of recurrent miscarriage who conceived naturally to progesterone supplementation initiated after a positive pregnancy test or placebo. Progesterone therapy was not shown to decrease miscarriage risk (76). Subsequently, a recently updated Cochrane review of progestogen for preventing miscarriage in women with recurrent miscarriage analyzed nine randomized trials of which seven compared progestogen to placebo or no treatment and found no significant benefit of progestogen supplementation on pregnancy outcome (77). The data on the use of progesterone supplementation for recurrent pregnancy loss may not necessarily be reflective of patients with LPD.

FUTURE DIRECTIONS

Despite LPD being proposed as a clinical entity causing infertility and early pregnancy loss for >70 years, there is a lack of quality research on the diagnostic criteria and treatment of LPD. Controversy remains regarding the definition, diagnosis, and clinical significance of LPD outside of a known pathologic condition suppressing LH pulsatility. There is a need for research to determine if isolated LPD is a clinical entity that leads to infertility. If LPD can be proven, then further research to develop diagnostic tests that differentiate fertile from infertile women with LPD is needed. Finally, randomized trials could be performed to evaluate therapeutic options for women with proven LPD. Present limited data do not support LPD as a clinical entity that causes infertility or early pregnancy loss, or that treatment can improve clinical outcomes.

SUMMARY

• Luteal phase deficiency is a clinical diagnosis and may be present with a luteal phase ≤10 days in length.
• Abnormal luteal function may occur as the result of several medical conditions.
• True isolated LPD implies an underlying pathologic abnormality of the luteal phase in the absence of an identifiable disease process negatively affecting normal LH support of the corpus luteum.
• No diagnostic test for LPD has been proven to be reliable in the clinical setting or in differentiating fertile from infertile women.
• Endometrial biopsies only have the precision to distinguish the early-, mid-, and late-luteal phases, and they have not been shown to discriminate between fertile and infertile women.
• No treatment for LPD has been shown to improve pregnancy rates in natural, unstimulated cycles.
• Progestogen supplementation has not been shown to benefit pregnancy outcomes in women with unexplained recurrent miscarriage.
• Infertile women suspected of having abnormal luteal function because of an underlying medical condition should be evaluated and treated appropriately for an identified abnormality.
• Histological dating of the endometrium with endometrial biopsies is not recommended.
• Additional research is needed to determine if testing modalities, such as combined testing (i.e., luteal progesterone measurement and luteal phase length <10 days for the diagnosis of LPD), identifies a subgroup of patients with poorer reproductive outcomes and, if so, whether treatment improves outcomes.
• Any evaluation for underlying causes of LPD should be initiated following shared decision making.
  
  

ACKNOWLEDGMENTS

This report was developed under the direction of the Practice Committee of the American Society for Reproductive Medicine (ASRM) as a service to its members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations. The Practice Committee and the Board of Directors of the American Society for Reproductive Medicine have approved this report. This document was reviewed by ASRM members, and their input was considered in the preparation of the final document.

The following members of the ASRM Practice Committee participated in the development of this document: Clarisa Gracia, M.D., M.S.C.E.; Tarun Jain, M.D.; Suleena Kalra, M.D., M.S.C.E.; Bruce Pier, M.D.; Denny Sakkas, Ph.D.; Belinda Yauger, M.D.; Rebecca Flyckt, M.D.; Torie C. Plowden, M.D., M.P.H.; Ryan Smith, M.D.; Suneeta Senapati, M.D.; Robert Brannigan, M.D.; Amy Sparks, Ph.D., H.C.L.D; Jared Robins, M.D.; Chevis N Shannon, Dr.Ph., M.B.A., M.P.H.; Jessica Goldstein, R.N.; and Madeline Brooks, M.B.A., M.P.H. The Practice Committee acknowledges the special contributions of Mark Trolice, M.D., M.B.A., and Karl Hansen, M.D., Ph.D, in the preparation of this document. All committee members disclosed commercial and financial relationships with manufacturers or distributors of goods or services used to treat patients. Members of the Committee who were found to have conflicts of interest on the basis of the relationships disclosed did not participate in the discussion or development of this document.

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