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Luteal Phase Deficiency – Its role in reproductive medicine and pregnancy loss

The term Luteal Phase Deficiency is often used by patients and clinicians in patients suffering from infertility and in the discussion of luteal phase deficiency the following questions will be answered in order to better understand this condition and its relevance to daily practice:

  1. What is luteal phase deficiency (LPD)?
  2. How common is luteal phase deficiency?
  3. Does luteal phase deficiency play a role in infertility?
  4. How can luteal phase deficiency be diagnosed?
  5. Can luteal phase deficiency be treated?

In order to give clinicians and patients guidance regarding this condition, the Practice Committee of the American Society for Reproductive Medicine (ASRM) published a committee opinion in November 2012 with the title: The clinical relevance of LPD, a committee opinion. This article summarizes the document which serves as the basis for clinical practice.

1. Introduction – what is LPD?

LPD has been described as a condition in which endogenous progesterone is not sufficient to maintain a functional secretory endometrium and allow normal embryo implantation and growth. During the normal menstrual cycle the first part of the cycle is known as the follicular phase in which gonadotropins (hormones from the pituitary) is secreted in a pulsatile way. These gonadotropins are responsible for stimulating the ovaries to produce follicles which will produce estrogen to prepare the endometrium for later implantation in the second half of the cycle (luteal phase).

During mid-cycle ovulation occurs after an increase in estrogen, which will induce aLH (Luteal Hormone) peak after which ovulation will occur 24—36 hours later.

The second half of the cycle after ovulation is known as the luteal phase. Normal luteal function requires optimal pre-ovulatory follicular development, luteinisation of the granulosa cells from the corpus luteum to produce progesterone and oestrogen in sufficient concentrations to induce progesterone receptors in the endometrium for implantation. A normal life span of the corpus luteum is 14 days unless rescued by the pregnancy hormone (human chorionic gonadotropin).

2. How common is LPD?

This ill-defined condition was first described in 1949 and was then called LPD after patients were observed with premature onset of menses due to low progesterone concentrations in the second half of their cycles. Today LPD is defined as a luteal phase shorter than 11 days or a lap of more than 2 days in endometrial histological development or low mid-luteal serum progesterone levels. As early as 1991 researchers (Jones1991) demonstrated that administration of exogenous progesterone could correct the luteal deficiency. Maintenance of pregnancy requires production of progesterone from the corpus luteum following ovulation and during early first trimester until placental function is established around 8-10 weeks. Thereafter the placenta is a functional unit responsible for progesterone secretion amongst its various functions. Removal of corpus luteum prior to the development of adequate placental function results in spontaneous pregnancy loss.

In the medical literature there exists controversy on the relevance of luteal phase and whether LPD even exists. This is partly due to the lack of a reliable tests to diagnose this disorder.

3. Does LPD play a role in infertility?

Whether LPD plays a role in reproductive outcome is still uncertain. Although there appears to be an association with infertility, it is not established that persistent LPD is a cause of infertility. Moreover it is important to note that LPD is only clinically relevant if it is consistently present in most cycles. LPD has been associated with the following clinical conditions:

  1. Infertility
  2. First trimester pregnancy loss
  3. Short cycles & pre-menstrual spotting

Risk factors for this condition may include anorexia nervosa, states of starvation as well as other eating disorders, excessive exercise, stress, obesity and PCOS, endometriosis, ageing as well as certain medical conditions i.e. 21-Hidroxylases deficiency, thyroid dysfunction and raised levels of prolactin (Hyperprolactinemia). It is also common in the first few months following pregnancy.

Certain medical treatment modalities may also be associated with LPD including ovarian stimulation, ovulation induction with or without GnRH agonists and several forms of assisted reproductive technology (ART). Although not all the possible medical conditions responsible for LPD will be discussed, it is important to know that endocrine conditions namely thyroid and prolactin disorders may disrupt the secretion of the Gonadotropin-releasing hormone (GnRH) from the hypothalamus. This alters the hypothalamic-pituitary-ovarian axis (the communication from the central to target organ endocrine communication). Increased secretion of thyroid releasing hormone from the pituitary in patients with underactive thyroid (Hypothyroidism) may also cause high levels of prolactin secretion by stimulating prolactin production and secretion.

The second condition that needs to be mentioned is that of obesity. Obesity has been associated with lower pregnancy rates and an increase in pregnancy loss.  This effect has been well described and is more important for patients with a BMI above 35. Changes in the patient’s weight is also important when it comes to LH pulsatile secretion and patients with a low BMI (less than 18) who is anorexic does have a significant reduction in the luteal phase progesterone production.

As with all aspects of reproductive outcome, ovarian ageing also has an effect on the luteal phase support of the endometrium. Early studies regarding the effect of ageing and progesterone production has shown that deficiencies in both luteal phase progesterone and estradiol have been identified in women of late reproductive age. LPD may also reflect a deficiency in the uterine endometrial response to normal hormonal changes during the luteal phase; this may be more expressed in the older patient.

4. How can luteal phase deficiency be diagnosed?

In order to understand any medical condition the pathophysiology (underlying mechanism of the disease process) needs to be clear in order to devise treatment modalities and the necessity of having effective screening tests in order to diagnose the condition. The pathophysiology of luteal inadequacy may include several different mechanisms that ultimately affect endometrial development.A short luteal phase was initially described as an interval of 8 or fewer days from a LH peak to the onset of the menstrual flow.  It is important to note however that a short luteal phase may occur in young healthy women with regular cycles. The diagnostic criteria for inadequate luteal function is based upon the following normal physiological observations:

  1. Normal LP length is relatively fixed at 14 days
  2. Progesterone levels peak in non-pregnant cycles 6-8 days after ovulation
  3. Progesterone is secreted in pulses
  4. The endometrial response is a reflection of the follicular phase estrogen and the luteal phase estrogen and progesterone
  5. Once implantation occurs, progesterone secretion by the corpus luteum is dependent on rising HCG levels coming from the conceptus
  6. Failure of HCG levels to increase directly causes corpus luteum failure and a decline in progesterone levels

Several methods have been proposed for making the diagnosis of luteal phase deficiency.  As with all medical conditions, certainly some of these tests are invasive and needs laboratory monitoring. Basal body temperature charting is the least invasive and serum progesterone levels in the luteal phase as well as endometrial biopsy have been studied.

Basal Body Temperature Charts: Because of the inaccuracy and inconvenience to patients, the measurements of BBT is of poor clinical significance and should be discouraged (ASRM Practice Committee Document recommendation).

Regarding monitoring of progesterone levels, it is important to note that progesterone is secreted in pulses that reflect LH pulses and levels may fluctuate up to 8 fold within 90 minutes. In order to determine the progesterone levels it is necessary to determine the time of ovulation and this is often clinically difficult. There is no minimal serum progesterone concentration that defines the fertile luteal function. It is also important to note that Corpus Luteum function varies from cycle to cycle in normal fertile woman; therefore random serum-progesterone levels are not a valid clinical diagnostic tool to evaluate Luteal Phase deficiency. (ASRM Practice committee Recommendation). The only value that serum progesterone in early pregnancy may have is in order to determine if the pregnancy is non-viable or possibly extra uterine (Ectopic, tubal.) Low progesterone levels in early pregnancy reflect abnormal HCG stimulation of the corpus luteum via a non-viable or extra uterine pregnancy. A low progesterone level after early pregnancy has been diagnosed should not be used to initiate therapy with progesterone (ASRM Practice Committee recommendation).

Another method, although invasive, that has been used as the gold standard to diagnose luteal inadequacy has been the endometrial biopsy. This is a procedure that is performed in the consulting room and is much the same as that of a pap smear. A thin curette is introduced into the cervix and with a suction curette tissue is sampled from the endometrium. This has been described by Noyes in 1975 and has served as the basis for histological evaluation (dating) of the endometrium.

In the past, studies that used the diagnostic criteria of luteal phase deficiency relied upon the traditional microscopic appearance of LP endometrial development. Recent prospective clinical trials suggest that the endometrial biopsy is an imprecise tool for differentiating fertile women from women with LPD. Recently two randomized trials of healthy regularly menstruating fertile women, demonstrated that endometrial maturation was delayed in up to 25 % of biopsy cycles and the variability for individuals from the one cycle to the next was high as well as high variability between pathologists. This confirms that the endometrial biopsy for the histological endometrial dating is not a valid clinical tool for the identification of an infertile population or diagnosis of LPD (ASRM Practice Committee Recommendation).

Many other histological as well as biochemical tools have since been devised but no proposed marker of receptivity has been validated to confirm its accuracy in distinguishing normal fertile women from  infertile women.

Molecular markers of receptivity remain experimental and are not valid clinical tools. The ASRM opinion is that there is currently no reproducible physiological relevant and clinical practical standard to diagnose LPD and distinguish fertile women from infertile women. The roles of BBT, luteal progesterone levels, endometrial biopsy and other diagnostic studies have not been established and performance of this test cannot be recommended (ASRM Recommendation).

5. Can luteal phase deficiency be treated?

Although this condition, whether it actually exists or not, cannot be accurately diagnosed, is there any potential treatment that may alter the outcome in patients with LPD?

As with other medical conditions the first approach to the treatment should be the correction of any underlying condition, this includes thyroid dysfunction as well as raised prolactin levels and in treating these conditions ovulation may be re-established with normal LP. It is also important to normalize weight and lifestyles changes, including diet, exercise and management of stress should be advised to all patients.

In the absence however of the mentioned screening tools, the treatment is empiric and is based on very limited reliable data. In the past treatment has been given empirically to promote the endometrial maturation as well enhancing endometrial receptivity and to support the implantation and development of early pregnancy. Strategies that are still implemented include supplemental progesterone, progesterone plus estrogen as well as human chorionic gonadotropin (hCG) in the LP. Ovulation induction with Clomiphene or gonadotropins has also been suggested.

Summary

While progesterone is important for the process of implantation and early embryonic development, Luteal Phase Deficiency, as an independent entity causing infertility, has not been proven.

Causes of abnormal luteal function may include medical conditions especially thyroid and prolactin disorders and infertile women should be investigated for these conditions and where indicated, treated with appropriate therapy.

No diagnostic tool for LPD has been proven reliable in clinical practice. The roles of BBT, luteal progesterone levels, endometrial biopsy for endometrial dating, and other diagnostic studies have not been established, and performance of these tests cannot be recommended.

No treatment for LPD has been shown to improve pregnancy outcomes in natural, unstimulated cycles.

There is no proven role in adding progesterone or hCG for luteal support once a pregnancy has been established and the use of supplemental progesterone in a non-ART cycle beyond the expected day of menses has not been proven beneficial.

Reference: The clinical relevance of luteal phase deficiency: a committee opinion. The practice committee of the American Society for Reproductive Medicine. Fertile steril 2012;98: 1112-1117

– With thanks to Dr Danie Botha from Fembryo clinic in Port Elizabeth

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