eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility

Luteal Phase Dysfunction

Thomas L Alderson, DO, Program Director, Assistant Professor, Department of Obstetrics and Gynecology, Mount Clemens Regional Medical Center, Michigan State University College of Osteopathic Medicine

Updated: Oct 8, 2008

Introduction

Background

In 1949, Georgeanna Jones, MD, first described luteal phase deficiency (LPD).⁹ 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.

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

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 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.

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.

Clinical

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.

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.

Differential Diagnoses

Hyperprolactinemia
Polycystic Ovarian Syndrome
Thyroid Disease

Workup

Laboratory Studies

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.

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 luteal phase deficiency.

Procedures

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.

Treatment

Medical Care

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.
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 endometrial biopsy to determine that LPD has been corrected.

Medication

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

Hormone replacements

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

Bromocriptine (Parlodel)

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

Dosing

Adult

1.25 mg (ie, half of 2.5-mg tab) PO qd; increase to 2.5 mg/d after 2 wk; repeat EB after prolactin level in reference range is achieved, to document correction of LPD

Pediatric

Not established

Interactions

Toxicity may increase with ergot alkaloids; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease bromocriptine effects

Contraindications

Documented hypersensitivity; ischemic heart disease; peripheral vascular disorders

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic disease

Levothyroxine (Levoxyl, Synthroid)

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

Dosing

Adult

1.6-1.9 mcg/kg ideal body weight PO; repeat TSH and T4 in 6-8 wk to determine if dose adjustment needed; once normalization achieved, repeat EB to confirm correction of LPD

Pediatric

Not established

Interactions

Cholestyramine may decrease liothyronine absorption; estrogens may decrease response to thyroid hormone therapy in patients with nonfunctioning thyroid glands; effect of anticoagulants increased when administered with liothyronine; activity of some beta-blockers may decrease when patients who have hypothyroidism are converted to a euthyroid state

Contraindications

Documented hypersensitivity; uncorrected adrenal insufficiency

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Caution in angina pectoris or cardiovascular disease; monitor thyroid status periodically

Clomiphene citrate (Clomid, Serophene)

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.

Dosing

Adult

Initial: 50 mg PO qd from days 5-9 of menstrual cycle; if repeat EB does not confirm correction of LPD, then increase in 50-mg doses (ie, 100 mg, 150 mg); no increment in dosage necessary once correction of LPD accomplished

Pediatric

Not established

Interactions

Danazol may reduce response to clomiphene

Contraindications

Documented hypersensitivity; liver disease; abnormal uterine bleeding; uncontrolled thyroid or adrenal dysfunction

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Visual symptoms and abdominal pain may occur

Cabergoline (Dostinex)

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

Dosing

Adult

0.5-3.0 mg PO 2 times/wk; once prolactin level is within reference range, repeat EB to confirm correction of LPD

Pediatric

Not established

Interactions

May increase effects of antihypertensive medications (adjust dose accordingly); dopamine agonists may reduce effects of cabergoline

Contraindications

Documented hypersensitivity; uncontrolled hypertension

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Concomitant use with hypertensives; do not use to inhibit physiologic lactation due to relatively high incidence of stroke, seizures, and hypertension; monitor prolactin levels monthly; caution in hepatic impairment

Progesterone (Crinone Vaginal Gel, Progestasert)

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.

Dosing

Adult

Vaginal gel: Apply qd/bid
Oil: 25 mg IM bid

Pediatric

Not established

Interactions

Aminoglutethimide may decrease effects

Contraindications

Documented hypersensitivity; thrombophlebitis, carcinoma of the breast, undiagnosed vaginal bleeding

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Fluid retention may occur; caution in patients with history of depression, impaired liver function, diabetes, and epilepsy; monitor for loss of vision, proptosis, diplopia, migraine, signs of embolic disorders

Follitropins (Follistim, Gonal-F, Fertinex)

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

Dosing

Adult

75 IU IM; increase to desired follicular response

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; ovarian failure, uncontrolled thyroid or adrenal dysfunction, tumor of the ovary, breast, uterus, hypothalamus, or pituitary; undiagnosed vaginal bleeding; ovarian cystic enlargement not due to polycystic ovarian disease

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Ovarian enlargement may be accompanied by abdominal distention; serious respiratory distress, thromboembolic events, atelectasis may occur

Follow-up

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.

Inpatient & Outpatient Medications

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 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.

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

Medicolegal Pitfalls

Failure to consider the diagnosis of luteal phase deficiency when seeing a patient with infertility or recurrent pregnancy loss

Special Concerns

The best treatment of luteal phase deficiency 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 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.²¹ 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 luteal phase deficiency occurs through an open and honest discussion between the physician and patient.

References

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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].
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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].
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Keywords

luteal phase dysfunction, LPD, luteal phase deficiency, luteal phase defect, progesterone, infertility, recurrent pregnancy loss

Contributor Information and Disclosures

Author

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

A David Barnes, MD, PhD, MPH, FACOG, Consulting Staff, Department of Obstetrics and Gynecology, Mammoth Hospital, Mammoth Lakes, California, Pioneer Valley Hospital, Salt Lake City, Utah, Warren General Hospital, Warren, Pennsylvania and Mountain West Hospital, Tooele, Utah
A David Barnes, MD, PhD, MPH, FACOG is a member of the following medical societies: American College of Forensic Examiners, American College of Obstetricians and Gynecologists, American Medical Association, Association of Military Surgeons of the US, and Utah Medical Association
Disclosure: Nothing to disclose.

CME Editor

Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Hancock Medical Center
Frederick B Gaupp, MD is a member of the following medical societies: American Academy of Family Physicians
Disclosure: Nothing to disclose.

Chief Editor

Bryan D Cowan, MD, Professor and Chairman, Department of Obstetrics and Gynecology, University of Mississippi College of Medicine; Consulting Staff, Department of Obstetrics and Gynecology, Veterans Affairs Medical Center; Medical Director, Wiser Hospital for Women, University of Mississippi Medical Center
Bryan D Cowan, MD is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Gynecological and Obstetrical Society, American Medical Association, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Endocrine Society, Sigma Xi, Society for Assisted Reproductive Technologies, Society for Gynecologic Investigation, Society for the Study of Reproduction, and Society of Laparoendoscopic Surgeons
Disclosure: Galil None Consulting

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