Luteal phase deficiency: ultrasonic and biochemical insights into pathogenesis

Serial ovarian ultrasound and daily assessments of plasma concentrations of pituitary and ovarian hormones were used to investigate ovarian function in 175 women with unexplained infertility. Their endocrine and ultrasound profiles were compared with similarly derived data from 43 normal volunteers. Fifty-one (29.1%) of the study group showed subnormal luteal phase rises in progesterone concentrations, described as poor progesterone surge (PPS) cycles. Within this group, 23 women (45.1%) demonstrated luteal cyst formation, a pattern not seen in any of the control cycles. High concentrations of follicle stimulating hormone (FSH) and reduced concentrations of oestradiol (E2) were observed in the follicular phases of the PPS cycles suggesting that the phenomenon is a product of abnormal follicular metabolism. An association of PPS with infertility exists, perhaps related to a combination of disturbances in the follicular micro-environment compromising oocyte quality, a failure of oocyte release, and impaired endometrial receptivity.     

Luteal phase deficiency after completely normal follicular and periovulatory phases

Luteal phase defect (LPD) accounts for a significant proportion of reproductive disorders, however its etiology is still debated. A prospective study was performed on 37 ovulatory women to determine whether LPD can occur in cycles characterized by completely normal folliculogenesis. Criteria for normal folliculogenesis included: a gradual rise of serum estradiol, a luteinizing hormone (LH) surge, the presence of a dominant follicle that disappeared, an increase of serum progesterone, and normal serum levels of prolactin, testosterone, dehydroepiandrosterone sulfate, follicle-stimulating hormone, and LH. Thirty of 37 women fulfilled the above mentioned strict criteria and underwent endometrial biopsy in the late luteal phase. Seven of 30 (23%) demonstrated a delay in endometrial development and all had normal hormonal and ultrasonographic parameters of folliculogenesis and ovulation. Women with delayed endometrial development demonstrated slightly longer follicular phases (17.0 +/- 1.1 versus 14.5 +/- 0.3 days). Perfectly normal follicular and periovulatory events may be followed by deficient luteal phases.     

Luteal phase deficiency: ultrasonic and biochemical insights into pathogenesis

Summary. Serial ovarian ultrasound and daily assessments of plasma concentrations of pituitary and ovarian hormones were used to investigate ovarian function in 175 women with unexplained infertility. Their endocrine and ultrasound profiles were compared with similarly derived data from 43 normal volunteers. Fifty-one (29·1%) of the study group showed subnormal luteal phase rises in progesterone concentrations, described as poor progesterone surge (PPS) cycles. Within this group, 23 women (45·1%) demonstrated luteal cyst formation, a pattern not seen in any of the control cycles. High concentrations of follicle stimulating hormone (FSH) and reduced concentrations of oestradiol (E2) were observed in the follicular phases of the PPS cycles suggesting that the phenomenon is a product of abnormal follicular metabolism. An association of PPS with infertility exists, perhaps related to a combination of disturbances in the follicular micro-environment compromising oocyte quality, a failure of oocyte release, and impaired endometrial receptivity.     

Luteal phase deficiency: effect of treatment on pregnancy rates.

Luteal phase deficiency is thought to be a cause of female infertility. Nevertheless, little agreement exists concerning either its diagnosis or its treatment. To address the latter question, we reviewed the English literature and examined the effect of treatment on pregnancy rates. One randomized controlled trial found a statistically insignificant benefit of treatment with progesterone suppositories or oral dehydroprogesterone versus no treatment (relative risk 1.9; 95% confidence interval 0.4 to 8.1). Three other comparative studies also showed no statistically significant benefit. Case-series reports (before-after studies) claiming benefit failed to account for the effect of regression to the mean. The benefit of treatment for luteal phase deficiency has not been established. Uniform case definitions and randomized controlled trials of adequate power are needed to resolve this problem.     

Luteal phase deficiency. An underdiagnosed and overtreated reproductive endocrine disorder

Although luteal phase deficiency is rather time consuming, expensive, and sometimes painful to diagnose and treat, this disease entity is associated with a high degree of treatment success. Physicians are encouraged to become more aware of luteal phase deficiency as a potential diagnosis in the infertile woman. If the recommendations are followed in the diagnosis and treatment of luteal phase deficiency, a high degree of success can be achieved in infertile couples who otherwise would be diagnosed as having idiopathic infertility (and be ineffectively treated).     

Luteal phase support

Assisted reproductive techniques have become a routine treatment for infertility. The extended use of gonadotrophin-releasing hormone analogues in assisted reproductive techniques has made luteal phase support mandatory, as it has been clearly demonstrated that they alter luteal LH pulsatility. For luteal support, HCG administration, though effective, has a high risk of ovarian hyperstimulation syndrome. Progesterone continues to be the gold standard for supplementation. Vaginal progesterone represents a highly effective alternative to painful intramuscular injections. The vaginal route is mainly characterized by direct delivery of the progesterone to the endometrium, thus producing high levels at the target tissue and a very low incidence of side effects.     

Luteal phase support

OBJECTIVE: To develop a consensus regarding the need for luteal phase support during assisted reproductive technology (ART), and to establish the optimal compound and route of administration for this purpose. DESIGN: Review of the published literature on luteal phase support. PATIENT(S): Women undergoing assisted reproductive technologies.Intervention(s): Progesterone was administered orally, vaginally, or by intramuscular (i.m.) injection to supplement the luteal phase after assisted reproductive technology (ART). MAIN OUTCOME MEASURE(S): Pregnancy following ART. RESULT(S); Gonadotropin releasing hormone (GnRH)-agonist protocols necessitate the use of luteal phase support. Progesterone and human chorionic gonadotrophin (hCG) have both been used for this purpose, with comparable outcomes. Progesterone is the product of choice, however, as it is associated with a lower incidence of ovarian hyperstimulation syndrome (OHSS). Its use is indicated up to the serum pregnancy test. Oral, i.m., and vaginal progesterone preparations are available. Intramuscular and vaginal preparations lead to comparable rates of implantation and clinical pregnancy, despite higher serum progesterone levels after i.m. injection. Oral formulations are inferior products for luteal support. Although widely used, i.m. progesterone is uncomfortable and inconvenient for patients. By contrast, the vaginal progesterone gel (Crinone 8%) is more convenient and easier to use. CONCLUSION(S): Progesterone support of the luteal phase in in vitro fertilization (IVF) cycles is indicated, though support beyond the serum pregnancy test may not be needed. The pregnancy rates after vaginal and i.m. progesterone support are comparable, despite higher serum levels after i.m. injection. Patients prefer the vaginal progesterone gel.     

Luteal phase deficiency: an inadequate endometrial response to normal hormone stimulation

Two hundred seventy-four infertile patients and 43 women with two or more previous first-trimester abortions underwent a luteal function evaluation by basal body temperature, plasma progesterone, estradiol and prolactin determination, and endometrial biopsy (repeated in a later cycle when the first was defective). An endometrial luteal phase deficiency was detected in 37 (13.5%) of the infertility cases and in 14 (32.5%) of the patients with recurrent miscarriage. However, the endometrial defect was associated with normal hormonal levels in the great majority of patients (86.3%).     

Luteal phase after ovarian hyperstimulation

The luteal phase was investigated in 17 women with normal menstrual cycles and tubal infertility who were superovulated with clomiphene (9 cycles), clomiphene plus pulsatile human menopausal gonadotrophin (hMG) (12 cycles) and clomiphene plus pulsatile follicle stimulating hormone (FSH) (11 cycles) during an in-vitro fertilization programme. Follicles were aspirated 34-36 h after the onset of the endogenous LH surge. Urinary total oestrogen levels during the first 6 days of the luteal phase were significantly higher, the duration of the luteal phase was significantly shorter and the luteal levels of urinary pregnanediol were significantly lower in the two combination treatment cycles than in the clomiphene only cycles. When the three treatment groups were combined the mid-luteal peak pregnanediol levels and the duration of the luteal phase showed significant negative correlations with plasma or urinary oestrogen levels during the follicular and the luteal phase. It is suggested that the luteal function in cycles superovulated with clomiphene/hMG or clomiphene/FSH is disrupted and this is related to the high amounts of circulating oestrogen.     

Luteal phase pregnancy and tubal sterilization

The effectiveness of several measures that may reduce the risk of luteal phase pregnancies after interval tubal sterilization was analyzed. Using data from the Collaborative Review of Sterilization on 5495 women, 18 luteal phase pregnancies were identified. Women who underwent sterilization after their estimated date of ovulation had a low risk of having a luteal phase pregnancy if they used oral contraceptives or an intrauterine device in the month before sterilization. Of the 18 luteal phase pregnancies, 14 (78%) occurred among the 16.8% of the women who were sterilized after their estimated date of ovulation and who had used barrier, rhythm, or withdrawal methods of contraception in the month before sterilization. The use of concurrent dilatation and curettage in these women at increased risk of luteal phase pregnancy did not lower their risk to that of women who were sterilized before their estimated date of ovulation.     

Luteal phase defects in repeated abortion

Fifty women with 2 or more previous first-trimester abortions and 300 infertile patients underwent a luteal phase evaluation by basal body temperature, plasma progesterone, estradiol and prolactin determination, and endometrial biopsy (repeated in a later cycle when the first was defective). An endometrial luteal phase deficiency was detected in 15 (30%) of aborting patients. In 13 (26%) of these women the endometrial defect was associated to normal hormonal levels. This condition was only present in 36 (12%) of the infertility cases (P less than 0.01). We conclude that the possible etiologic role of luteal phase defects in repeated abortion, is by a secretory insufficiency in the endometrial pattern despite normal plasma hormonal levels.     

Luteal phase defect: myth or reality

Although the diagnosis of luteal phase defect (LPD) has been described convincingly in the research setting, it remains a controversial clinical entity. Apart from many uncertainties that surround the diagnosis of LPD, there is no convincing evidence that LPD is associated with infertility and recurrent abortion. Once diagnosed, the treatment options are empiric and include those that are recommended for unexplained infertility. The efforts to diagnose LPD in patients who have infertility or recurrent abortion are not justified.     

Luteal phase support in assisted reproductive technology

PURPOSE OF REVIEW: The purpose of this review is to discuss luteal support in assisted reproduction and to provide an evidence-based overview of the current options available. RECENT FINDINGS: The luteal phase has been found to be defective in virtually all of the stimulation protocols used for in-vitro fertilization. Common mechanisms such as supraphysiological levels of estradiol, decreased output of luteinizing hormone, inhibition of the corpus luteum and asynchronization of estradiol and progesterone may be involved in insufficient function of the corpus luteum in assisted reproductive technology. SUMMARY: Gonadotropin releasing hormone agonist undoubtedly provides benefits in stimulated cycles, however it also has adverse effects, inhibition of the corpus luteum together with supraphysiological hormonal profiles finally leading to luteal phase defects. Luteal phase support with human chorionic gonadotropin or progesterone after assisted reproduction results in increased pregnancy rates. The role of luteal phase support in these cycles has also been recently elucidated. Use of human chorionic gonadotropin for luteal phase support is associated with a marked increase in the risk of ovarian hyperstimulation syndrome, therefore progesterone is the preferred choice. Data on the benefits of estrogen supplementation are conflicting. Among the routes of progesterone administration, reductions in pregnancy rates are noted on oral administration. In spite of a lack of statistical significance, the intramuscular route seems to be more beneficial than the vaginal route when considering rates of ongoing pregnancy and live birth. Further clarification is needed on the ideal dose, the optimal route and the duration of progesterone administration in assisted reproduction.     

Luteal phase evaluation after clomiphene-chorionic gonadotrophin-induced ovulation

Fifty infertile patients treated with clomiphene and hCG for induction of ovulation were studied with plasma progesterone measurement and endometrial histology. Five patients (10%) presented defective endometria and low plasma progesterone in spite of biphasic BBT charts with normal luteal phase length. Forty-five patients (90%) had significantly higher plasma progesterone concentrations than those found in a control group of fertile women, but a defective endometrial secretory pattern occurred in 19 of these 45 patients (42.3%). These data suggest the need for monitoring the response to clomiphene by endometrial histology in addition to BBT and plasma progesterone, or for supplemental therapy to overcome the endometrial luteal phase deficiency in clomiphene-treated cycles.