AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1949, Georgeanna Jones, MD, first described luteal phase deficiency (LPD). The inadequate secretory transformation of the endometrium, resulting from deficient progesterone production, has been implicated in both infertility and recurrent pregnancy loss. 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.

Pathophysiology

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

Abnormal follicular development

Abnormal follicular development results from inadequate follicle-stimulating hormone (FSH) and 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.

Frequency

United States

No consensus has been achieved regarding frequency; however, a 1991 symposium hypothesized that 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. See above.

Mortality/Morbidity

No morbidity or mortality has been associated with this condition.

Race

LPD affects women of all races.

Sex

LPD affects only women.

Age

LPD primarily affects women during their reproductive years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 LPD.

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.

Causes

See Pathophysiology for a full discussion of the causes.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Serum progesterone levels have been studied as a means to diagnose 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.

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. Ultrasound measurement of endometrial thickness has not been shown to be effective in the prediction of LPD.

Procedures

• Biopsy
• • In 1950, Noyes, Hertig, and Rock established that the diagnosis of LPD is centered on histologic dating of the endometrium. However, the location and time of the biopsy can greatly influence 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Hyperprolactinemia and hypothyroidism cause 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.
• Clomiphene citrate corrects LPD by improving folliculogenesis and the resultant luteal phase following ovulation. Successful treatment with gonadotropins and human chorionic gonadotropins (HCGs) probably results from superovulation rather than from a correction of LPD.
• Following any of these treatments, the patient should have a repeat EB to determine that LPD has been corrected.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Hormone replacements

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

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

Further Outpatient Care

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

In/Out Patient Meds

• 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.

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.

Complications

• Complications are associated with the EB. Be cautious when performing the biopsy in order 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.

Prognosis

• The lack of double-blinded placebo-controlled studies prevents an accurate prognosis for this condition.

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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider the diagnosis when seeing a patient with infertility or recurrent pregnancy loss

Special Concerns

• The best treatment is not yet established because of the lack of double-blinded placebo-controlled studies with an adequate number of patients from whom appropriate conclusions can be made. The overall conclusion is that luteal phase dysfunction (LPD) does exist, but the endometrial biopsy is not sufficient to diagnose the defect. The defect may be at a molecular level and specific markers are needed. Research on molecular defects have found such abnormalities in the endometrium in women with endometriosis, polycystic ovarian syndrome, and hydrosalpinx. Taylor has shown diminished HOXA10 gene expression in these women. Endometrial receptivity may depend on gene expression that may be regulated by estrogen and progesterone. Until investigators can resolve these issues, the decision to treat patients with LPD occurs through an open and honest discussion between the physician and patient.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Behrman HR, Endo T, Aten RF. Corpus luteum function and regression. Reprod Med Rev. 1993;2:153-80.
• Cermik D, Selam B, Taylor HS. Regulation of HOXA-10 expression by testosterone in vitro and in the endometrium of patients with polycystic ovary syndrome. J Clin Endocrinol Metab. Jan 2003;88(1):238-43.
• Cicinelli E, de Ziegler D, Bulletti C, et al. Direct transport of progesterone from vagina to uterus. Obstet Gynecol. Mar 2000;95(3):403-6. [Medline].
• Cooke ID. The corpus luteum. Hum Reprod. Feb 1988;3(2):153-6. [Medline].
• Csapo AI, Pulkkinen MO, Ruttner B et al. The significance of the human corpus luteum in pregnancy maintenance. I. Preliminary studies. Am J Obstet Gynecol. Apr 15 1972;112(8):1061-7. [Medline].
• Daftary GS, Taylor HS. Hydrosalpinx fluid diminishes endometrial cell HOXA10 expression. Fertil Steril. Sep 2002;78(3):577-80.
• Giudice LC. Growth factors and growth modulators in human uterine endometrium: their potential relevance to reproductive medicine. Fertil Steril. Jan 1994;61(1):1-17. [Medline].
• Healy DL, Schenken RS, Lynch A, et al. Pulsatile progesterone secretion: its relevance to clinical evaluation of corpus luteum function. Fertil Steril. Jan 1984;41(1):114-21. [Medline].
• Jones GES. Some newer aspects of management of infertility. JAMA. 1949;141:1123-1129.
• Jones GS. The luteal phase defect. Fertil Steril. Apr 1976;27(4):351-6. [Medline].
• Karamardian LM, Grimes DA. Luteal phase deficiency: effect of treatment on pregnancy rates. Am J Obstet Gynecol. Nov 1992;167(5):1391-8. [Medline].
• Li TC, Nuttall L, Klentzeris L, Cooke ID. How well does ultrasonographic measurement of endometrial thickness predict the results of histological dating?. Hum Reprod. Jan 1992;7(1):1-5. [Medline].
• McNeely MJ, Soules MR. The diagnosis of luteal phase deficiency: a critical review. Fertil Steril. Jul 1988;50(1):1-15. [Medline].
• Murray DL, Reich L, Adashi EY. Oral clomiphene citrate and vaginal progesterone suppositories in the treatment of luteal phase dysfunction: a comparative study. Fertil Steril. Jan 1989;51(1):35-41. [Medline].
• Noyes RW, Hertig AW, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1:3-25.
• Peters AJ, Lloyd RP, Coulam CB. Prevalence of out-of-phase endometrial biopsy specimens. Am J Obstet Gynecol. Jun 1992;166(6 Pt 1):1738-45; discussion 1745-6. [Medline].
• Peters AJ, Wentz AC. Luteal phase inadequacy. Seminars in Reprod Endo. 1995;13:162-171.
• Sherman BM, Korenman SG. Measurement of plasma LH, FSH, estradiol and progesterone in disorders of the human menstrual cycle: the short luteal phase. J Clin Endocrinol Metab. Jan 1974;38(1):89-93. [Medline].
• Shoupe D, Mishell DR Jr, Lacarra M, et al. Correlation of endometrial maturation with four methods of estimating day of ovulation. Obstet Gynecol. Jan 1989;73(1):88-92. [Medline].
• Soules MR (ed.). Luteal phase deficiency. Pitkin RM (ed.): Clinical Obstetrics and Gynecology. Vol 34, pp123-126. Philadelphia. JB Lippincott, 1991).
• Taylor HS, Bagot C, Kardana A, et al. HOX gene expression is altered in the endometrium of women with endometriosis. Hum Reprod. May 1999;14(5):1328-31.
• Yen SC, Jaffe RB, Barbieri RL. Luteal Phase Defects. In: Reproductive Endocrinology. 4th ed. 1999: 244-5.

Article Last Updated: Jun 13, 2006