Luteal Phase Dysfunction

Background

In 1949, Georgeanna Jones, MD, first described luteal phase deficiency (LPD).^[1] The inadequate secretory transformation of the endometrium, resulting from deficient progesterone production, has been implicated in both infertility and recurrent pregnancy loss.^{[2, 3]} LPD has been the subject of much debate among specialists in the field of reproductive endocrinology since Jones' introduction of this condition into the medical literature. LPD has been diagnosed in 3-20% of patients who are infertile and in 5-60% of patients experiencing recurrent pregnancy loss. However, data show that 6-10% of women who are fertile demonstrate an inadequate luteal phase, which confirms the need for a better understanding of normal variations in the menstrual cycle and in variations that could be pathologic.

This article addresses healthy menstrual physiology, the proposed pathophysiology of LPD, current methods available for diagnosis and treatment, and reasons for the controversy surrounding this subject.

Healthy menstrual physiology

Following ovulation, the mature ovarian follicle forms the corpus luteum, which becomes a blood-filled structure that allows the precursor cholesterol to be obtained, initiating steroidogenesis and resulting in progesterone production. Whereas the follicular phase of the menstrual cycle can vary in length, the secretory phase lasts approximately 14 days, correlating with the life span of the corpus luteum. Presumably, progesterone prepares the endometrium for implantation and maintenance of a pregnancy. If pregnancy occurs, the production of progesterone from the corpus luteum continues for 7 weeks because of the tonic release of luteinizing hormone (LH) from the pituitary gland. Studies show that after 7 weeks, the placenta takes over this function. If pregnancy does not occur, menses begins with the demise of the corpus luteum.

For related information, see Medscape's Pregnancy Resource Center.

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Pathophysiology

The following mechanisms can cause an inadequate endometrial response to hormonal stimulation during the luteal phase.^[4]

Abnormal follicular development

Abnormal follicular development results from inadequate follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion from the anterior pituitary gland. FSH stimulates the granulosa cells of the developing follicle to produce estradiol from the conversion of its substrate androstenedione. A decrease in FSH release results in reduced granulosa cell growth and lower estradiol levels. Because the corpus luteum is not a de novo structure but is a direct result of the follicle, it shows the effects of abnormal folliculogenesis with decreased progesterone production.

Abnormal luteinization

An inadequate LH release can cause a decrease in androstenedione from the theca cells. Less substrate results in a decrease in estradiol and, subsequently, lower progesterone levels. Additionally, a suboptimal LH surge at ovulation causes deficient progesterone because of inadequate luteinization of the granulosa cells.

Uterine abnormalities

Uterine abnormalities cause changes in vascularization of the endometrium despite normal progesterone levels. Myomas, uterine septa, and endometritis are responsible for poor secretory changes in the endometrium.

Hypocholesterolemia

Hypocholesterolemia is the substrate responsible for initiation of the steroid pathway. A deficiency results in low-to-absent progesterone production and a luteal phase defect.

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Epidemiology

Frequency

United States

No consensus has been achieved regarding frequency; however, a 1991 symposium hypothesized that luteal phase deficiency (LPD) occurs in 3-10% of infertile patients, and healthy women have deficient luteal phase production of progesterone on a sporadic basis.

International

Presumably, international frequency is similar to that in the United States.

Mortality/Morbidity

No morbidity or mortality has been associated with this condition.

Race

Luteal phase deficiency affects women of all races.

Sex

Luteal phase deficiency affects only women.

Age

Luteal phase deficiency primarily affects women during their reproductive years.

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History

The patient may report menstrual cycles of less than 26 days or a luteal phase of less than 11 days by basal body temperatures; however, neither of these circumstances can alone be used to diagnose luteal phase deficiency.

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Physical

Physical findings that might aid in the diagnosis of luteal phase dysfunction are those associated with abnormal endocrine function.

• An enlarged thyroid gland is indicative of hypothyroidism.
• Expression of milk from the breasts (galactorrhea) is indicative of hyperprolactinemia.
• An enlarged, irregularly shaped uterus is indicative of uterine myomas.

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Causes

See Pathophysiology for a full discussion of the causes.

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Laboratory Studies

See the list below:

• Serum progesterone levels have been studied as a means to diagnose luteal phase deficiency (LPD). Early data showed that peak progesterone production occurred in the mid-luteal phase. Later studies confirmed that progesterone is released in a pulsatile fashion, suggesting that a single sample is nondiagnostic. The use of multiple samples to overcome the pulsatile nature of progesterone is expensive and inconvenient.
• Urinary LH kits provide a useful test to estimate the appropriate timing of an endometrial biopsy (EB). Following a positive test finding, ovulation occurs within 24-26 hours. The EB should be performed on the 12th day of a 14-day luteal phase.
• Studies measuring progestin endometrial protein (PEP) have not been conclusive in diagnosing LPD. Studies regarding cell adhesion molecules or integrins, growth factors, and cytokines are all in the experimental phase.

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Imaging Studies

Ultrasound documentation of ovulation from follicular growth to collapse of the follicle is very accurate; however, this procedure is too expensive and time consuming to be realistic in all patients.^[5] Ultrasound measurement of endometrial thickness has not been shown to be effective in the prediction of luteal phase deficiency.

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Procedures

See the list below:

• Biopsy

  • In 1950, Noyes, Hertig, and Rock established that the diagnosis of luteal phase deficiency (LPD) is centered on histologic dating of the endometrium. However, the location and time of the biopsy can greatly influence endometrial biopsy (EB) findings. Some authors believe that mid-luteal phase biopsy is the best for accurate diagnosis of LPD.
  • Biopsies from the fundus of the uterus yield improved histologic samples compared to those taken from the lower uterine segment. Specimens taken approximately 1-2 days prior to menses provide better specimens for interpretation. For example, women with cycles of 28 days should have an EB performed on the 26th day.
  • Histologically, a luteal phase defect provides a biopsy that lags behind the date of actual endometrial sampling by 3 days or more. To confirm that such a result is not a variance within the reference range, the biopsy should be performed in 2 consecutive cycles; however, the discomfort associated with the biopsy causes difficulty in convincing the patient to have the procedure performed twice. Several methods can be used to time the EB just prior to menses. The basal body temperature (BBT) chart is one such method.
    • The BBT chart can aid in determining the length of the luteal phase. A luteal phase of less than 11 days may be associated with LPD.
    • The BBT chart can also assist in timing the EB by observing the patient's cycle length and performing the biopsy 2 days prior to the expected menses.
    • Although the BBT chart is easy and inexpensive, interpretation can be difficult and frustrating with a woman who is infertile or has suffered multiple pregnancy losses.

   

  

   

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Medical Care

See the list below:

• Hyperprolactinemia and hypothyroidism cause luteal phase deficiency (LPD) through hypothalamic-pituitary dysfunction.
• Bromocriptine and levothyroxine, respectively, are used to treat LPD in women with these conditions.
• In women without hyperprolactinemia and hypothyroidism, vaginal progesterone is advocated to supplement endogenous progesterone production. The vaginal suppository or gel is preferred over both the oral and intramuscular forms because of superior endometrial progesterone concentrations. Vaginal suppositories are less expensive but are messier than the vaginal gel. Progesterone should be continued for 8-10 weeks to cover the time of the ovarian-placental shift.
• A Cochrane review found that synthetic progesterone is preferred to micronized progesterone. The study also found that other substances, such as estrogen and human chorionic gonadotropin (hCG), did not improve outcomes. No specific route or duration was preferred.^[6]
• Clomiphene citrate corrects LPD by improving folliculogenesis and the resultant luteal phase following ovulation. Successful treatment with gonadotropins and HCGs probably results from superovulation rather than from a correction of LPD.
• Following any of these treatments, the patient should have a repeat endometrial biopsy to determine that LPD has been corrected.

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Medication Summary

The goals of pharmacotherapy in luteal phase deficiency are to restore ovarian function, reduce morbidity, and prevent complications.

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Bromocriptine (Parlodel)

• Dosing, Interactions, etc.

Clinical Context:  Used if hyperprolactinemia is the underlying pathology causing LPD. Tablets can be used vaginally in patients who cannot tolerate adverse GI effects.

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Levothyroxine (Levoxyl, Synthroid)

• Dosing, Interactions, etc.

Clinical Context:  If LPD is caused by hypothyroidism, correction of endocrine disease results in normal luteal phase.

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Clomiphene citrate (Clomid, Serophene)

• Dosing, Interactions, etc.

Clinical Context:  Stimulates release of pituitary gonadotropins. Improves folliculogenesis and, therefore, the luteal phase. Works best in biopsies that are lagging 1 week behind the date of endometrial sampling.

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Cabergoline (Dostinex)

• Dosing, Interactions, etc.

Clinical Context:  Long-acting dopamine receptor agonist with high affinity for D2 receptors. Prolactin secretion by anterior pituitary predominates under hypothalamic inhibitory control exerted through dopamine.

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Progesterone intravaginal gel

• Dosing, Interactions, etc.

Clinical Context:  Progesterone supplementation may be administered PO, IM, or vaginally. Oral progesterone is metabolized rapidly in liver, and the metabolites have little effect on endometrial activity. When administered IM, fails to achieve adequate levels of endometrial progesterone compared with vaginal forms. Vaginal progesterone is DOC for LPD; this is because of the proximity of the uterus to where the medication is delivered. Vaginal gel 8%, either qd or bid, is better tolerated compared to suppository form. Gel also provides increased receptor sites in the endometrium compared with suppository. Treatment begins 2 days after ovulation as determined by ovulation predictor kit. Correction of LPD can be confirmed by repeat EB.

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Follitropins (Follistim, Gonal-F, Fertinex)

Clinical Context:  Improve folliculogenesis, which increases total progesterone. This remains an expensive method associated with increased patient discomfort because medication is administered SC.

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Class Summary

Medical treatment centers on hormonal support of the patient's luteal phase.

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Further Outpatient Care

All diagnostic testing and treatment can be performed in an outpatient setting.

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Further Inpatient Care

Luteal phase dysfunction does not require hospitalization and therefore no inpatient diagnostic workup or treatment.

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Inpatient & Outpatient Medications

See the list below:

• Medications used to treat luteal phase dysfunction include dopamine receptor agonists to treat elevated serum prolactin levels.
• Thyroid replacement treats hypothyroidism.
• Supplemental progesterone increases the lower levels in the luteal phase observed with this condition.
• Clomiphene citrate enhances follicular development and thus increases luteal-phase progesterone levels.
• Human menopausal gonadotropins enhance follicular development and increase luteal-phase progesterone levels.

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Deterrence/Prevention

No methodology prevents luteal phase defect. Maintain a high level of clinical suspicion that such a condition exists when seeing a patient with infertility or recurrent pregnancy loss.

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Complications

Complications are associated with the endometrial biopsy. Be cautious when performing the biopsy to avoid perforating the uterus. Advise patients to take a nonsteroidal anti-inflammatory drug (NSAID) prior to the procedure to alleviate uterine cramping. No antibiotic prophylaxis is needed.

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Prognosis

The lack of double-blinded placebo-controlled studies prevents an accurate prognosis for this condition. A report by the Practice Committee of the American Society for Reproductive Medicine concluded that there is no significant evidence that LPD alone can cause infertility.^[7]

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Patient Education

Patients should keep an accurate menstrual cycle calendar. Abnormal cycle length may heighten the physician's suspicion that a luteal phase dysfunction exists.

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