Background:

Luteinizing hormone (LH), a 29,000–molecular weight (MW) glycoprotein produced by basophilic cells in the anterior pituitary, affects key biochemical changes critical to normal menstrual and ovulatory function in reproductive aged women. LH is released by the anterior pituitary in hourly pulses, which Deirsche et al termed as circhoral oscillations. This release is in response to pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the arcuate nucleus of the hypothalamus. GnRH was first isolated in 1970 and has a serum half-life of 20 minutes.

Sex steroids synthesized by the dominant follicle in the ovary modulate serum levels of LH. While both estrogen and progesterone play important roles in modulating the release of LH, estrogen is more significant in early follicular development and, ultimately, ovulation. Estrogen, specifically estradiol, normally inhibits LH secretion. However, when estrogen reaches a certain level, there is positive feedback to the anterior pituitary, resulting in an increase in circulating LH. This transition from suppression to stimulation of LH secretion takes place at the mid–follicular phase and is dependent on the absolute level and duration of elevation of serum estradiol. Estradiol levels must be greater than 200 pg/mL for 50 hours. This typically occurs when the dominant ovarian follicle reaches a diameter of 15 mm or greater. The direct effect of the mid–follicular estradiol peak is the LH peak. LH is critical to luteinization of the ovarian follicle, production of progesterone in the theca cells, and the postovulatory follicular function. If estrogen levels are not sustained at these levels, the mid cycle LH surge may be abbreviated or even fail to occur.

Luteal phase deficiency (LPD) describes a clinical condition in which insufficient luteal support exists during early pregnancy, most likely due to insufficient levels of progesterone in the latter part of the menstrual cycle. The diagnosis of LPD occurs with the aid of detection of a greater than 2-day difference between the histological dating and menstrual dating of the endometrium. Histological dating is obtained from an endometrial biopsy prior to menstruation.

Historically, when histologic dating of the endometrium differed from the date of the menstrual cycle by 2 or more days, the diagnosis of LPD was suspected. If this greater than 2-day difference was found in 2 or more cycles, the diagnosis was confirmed. This histologic difference was felt to be secondary to inadequate or ineffective progesterone support. More recently, the adequacy of the luteal phase has been assessed by measuring progesterone levels in the luteal phase. Single or multiple pooled values have been utilized between 21-24 days into the menstrual cycle. A progesterone level greater than 6.5 ng/mL is felt to represent adequate progesterone support from the corpus luteum. Most authors now agree that a single mid–luteal phase progesterone level is not sufficient to evaluate the adequacy of the luteal phase.

Finally, basal body temperature (BBT) charts are used to evaluate the adequacy of the luteal phase.Although primarily used to indicate ovulation, the sustained elevation of temperature in the luteal phase has been shown to be indicative of elevated serum progesterone. Progesterone is known to be thermogenic, and adequate luteal support in an ovulatory cycle maintains temperature elevations in the luteal phase.

Pathophysiology: The common endpoint in LPD is inadequate progesterone production by the developing corpus luteum. Ultimately, LPD leads to infertility by making the luteal phase endometrium inhospitable to the implanting blastocyst.

Mortality/Morbidity: Luteinizing hormone deficiency is not associated directly with any significant morbidity or mortality. This disorder may contribute to infertility and, in this way, may result in significant costs to society. LPD and chronic anovulation also may be associated with other medical problems.

Age: All reproductive-aged women can experience inadequate luteal phase support. Women at either end of their reproductive lives, just after menarche and just before menopause, have a higher incidence of luteal phase defect.

History: Women with luteinizing hormone deficiency generally are asymptomatic and typically have regular menstrual cycles.

Physical: No consistent physical findings exist in women with LPD.

Causes:

• The common endpoint in LPD is inadequate progesterone production by the developing corpus luteum or inadequate progesterone function.

• One possible etiology of LPD is inadequate estrogen in the follicular phase of the menstrual cycle. Estrogen in the follicular phase is responsible for priming the endometrial lining by inducing development of progesterone receptors in the endometrial cells. This inadequate preparation of the endometrial lining is one form of LPD.

• The lack of effective progesterone support also can result from inadequate production from the corpus luteum. This may be the common endpoint of abnormal patterns of LH secretion, lower levels of LH and follicle-stimulating hormone (FSH) at the time of the ovulatory surge, low levels of FSH in the follicular phase of the menstrual cycle, or, finally, decreased responsiveness of the endometrium to progesterone.

• Ultimately, LPD most likely contributes to infertility by making the luteal phase endometrium inhospitable to the implanting blastocyst.
  
  

Hyperthyroidism
Prolactinoma

• Luteal phase progesterone: Single or multiple pooled values have been utilized between 21-24 days into the menstrual cycle. A progesterone level greater than 6.5-10 ng/mL in the mid–luteal phase of the menstrual cycle represents adequate progesterone support from the corpus luteum. A single mid–luteal phase progesterone level is not sufficient to evaluate the adequacy of the luteal phase, and several values should be obtained.

• Obtaining baseline thyroid stimulating hormone (TSH) and prolactin levels is critical in evaluating patients who are infertile.

Imaging Studies:

• Ultrasound: Measuring endometrial thickness by ultrasound during the luteal phase has been used to assess the adequacy of luteal phase support from the corpus luteum.

• The thickness also has been shown to correlate with serum progesterone levels. A progesterone level greater than 15 ng/mL has been associated with an endometrial thickness of 11.8 mm.

• In contrast, patients with progesterone levels less than 15 ng/mL have an average thickness of 8.3 mm.

• The sonographic measurement of the thickness of the mid–luteal endometrium might serve as an additional criterion for the evaluation of the secretory phase of the menstrual cycle.

• A thin endometrial stripe is expected in patients with luteal phase deficiency; however, this value has yet to be quantified.

Other Tests:

• BBT charts are used to evaluate the adequacy of the luteal phase. Although primarily used to indicate the timing of ovulation, the sustained elevation seen in the luteal phase has been shown to correlate with an elevated serum progesterone level. Progesterone is known to be thermogenic. With adequate luteal support in an ovulatory cycle, it should maintain the temperature elevation between 11-16 days.

Procedures:

• When performed in the late luteal phase of the menstrual cycle, an endometrial biopsy can be used to diagnose luteinizing hormone deficiency. Historically, a lag of 2 or more days between the histologic development of the endometrium documented by endometrial biopsy and menstrual dating is evidence of LPD.

Medical Care:

• Whether or not the entity of LPD truly exists remains controversial. Treatment modalities also remain a source of contention. Medical management is the only choice of treatment for those diagnosed with luteinizing hormone deficiency. Surgical therapy has no role in this disorder.

• Two broad categories of treatment exist.

• The first approach attempts to improve the quality of the follicle and the process of ovulation. The reasoning for this approach is based on the understanding that inadequate progesterone produced in the luteal phase is due to a suboptimal rise in LH. In turn, the poor LH rise leads to the poor quality of the ovum that is released. Clomiphene citrate and gonadotrophins have been shown to be effective in this condition. Clomiphene citrate competes with endogenous estrogen to stimulate estrogen receptors in the hypothalamus. This provides a low estrogen signal that results in increased levels of FSH.

• The second approach to management of this clinical entity is to support the ovulatory cycle and early gestation with exogenous progesterone. The addition of progesterone helps to support the endometrial lining, normally maintained by endogenous progesterone from the corpus luteum. Several commercial preparations are available for this purpose.

Surgical Care: Surgical therapy has no role in this disorder.

• Gynecologists may need to consult the expertise or services of a reproductive endocrinologist.

Diet: No known association between diet or dietary deficiency and luteinizing hormone deficiency exist. Some conditions (eg, hyperlipidemia) associated with LPD may have specific dietary recommendations.

Activity: No known association exists between a patient's activity level and luteinizing hormone deficiency.

Therapies for patients with luteinizing hormone deficiency are synthetic progestational agents (progesterone) and ovulation induction agents (clomiphene citrate). In pregnancy rates, no demonstrable differences between these 2 drug choices exist.

Drug Category: Ovulation induction agents -- Induce ovulation

CLOMIPHENE CITRATE:

50 mg PO qd on days 3-7(or 5-9) of menstrual cycle.  

Drug Category: Progestational agents -- May support the luteal phase of a female who is subfertile in whom inadequate intrinsic luteal phase progesterone is available.

PROGESTERONE:

Vaginal suppository: 25 mg bid
Gel 8%: 1 applicator PV qd
Oral micronized: 100 mg PO tid
17-hydroxyprogesterone caproate: 250 mg IM qwk  

Prognosis:

• Patients with this disorder respond very well to medical management. Unfortunately, even with adequate luteal phase progesterone support, infertility remains a problem for a percentage of these patients.