Maintenance of pregnancy requires progesterone production by the corpus luteum after ovulation until placental function is established after the early trimester. Removal of the corpus luteum before full establishment of placental function will result in spontaneous abortion. Given the importance of ovarian progesterone production for implantation and early pregnancy, inadequate ovarian function may be the cause of infertility or pregnancy failure. Studies supporting the need for adequate progesterone in the luteal phase have shown that progesterone levels rise more rapidly in menstrual cycles in which conception occurs and that estrogen and progesterone levels are higher in the mid-luteal phase compared to those in which conception does not occur. However, the similar increase in luteal phase progesterone levels in normal and biochemical pregnancy cycles suggests that pregnancy loss is not always due to ovarian insufficiency. Delayed implantation is associated with a higher probability of pregnancy loss, and delayed implantation is more likely to result from early embryonic problems of inadequate human chorionic gonadotropin (hCG) production rather than from an improper ovarian response.
The luteal phase plays an important role in establishing a normal pregnancy, and luteal phasedeficiency (LPD) is a condition in which endogenous progesterone is insufficient to maintain a functional secretory phase endometrium for normal embryo implantation and growth. This disorder was first described in 1949 . The debate about the clinical significance of LPD is due to the lack of reliable tests to diagnose the disorder. Luteinizing insufficiency is allegedly associated with infertility, early pregnancy miscarriage, shortened menstrual cycles, premenstrual spotting, anorexia, hunger and eating disorders, excessive exercise, stress, obesity and polycystic ovary syndrome (PCOS), endometriosis, aging, poorly treated 21-hydroxylase deficiency, hypothyroidism and hyperprolactinemia, ovulation stimulation, use or non-use of gonadotropin-releasing agonists Ovulation stimulation and assisted reproductive technology (ART) have been associated. Studies have also shown that luteal insufficiency can occur during the postpartum period, with significant weight loss or exercise, and also in women with normal menstrual cycles. Although luteal insufficiency may be associated with infertility, there are no studies to confirm that persistent luteal insufficiency is the cause of infertility. Furthermore, if it persists through most menstrual cycles, LPD is only a clinically relevant problem. This report addresses the controversies that exist in the diagnosis and possible treatment of luteal insufficiency.
Clinical conditions with potential impact on luteal function
Abnormal pulsations of gonadotropin-releasing hormone (GnRH), follicle stimulating hormone (FSH) and luteinizing hormone (LH) can be found during recovery from hypothalamic amenorrhea, resulting in decreased luteal phase estrogen and progesterone production. Abnormal progesterone secretion due to reduced LH pulsations during the ovulatory cycle in hypothalamic amenorrheic women is also a difficult problem to manage.
Thyroid and prolactin dysregulation may also disrupt gonadotropin-releasing hormone secretion and alter the hypothalamic-pituitary-ovarian axis. Increased secretion of thyrotropin-releasing hormone in hypothyroidism stimulates the pituitary prolactin cells to produce and secrete prolactin, which causes hyperprolactinemia. Hyperprolactinemia can act on the neuronal prolactin receptors of GnRH to directly inhibit GnRH secretion, or indirectly inhibit GnRH secretion by increasing hypothalamic dopamine and opioid-like peptide levels. Other conditions associated with altered luteal phase progesterone levels include renal transplantation, increased beta-endorphin, and lactation. Disorders that alter normal gonadotropin secretion can affect follicular development and ultimately luteal function, and alterations in the amount and duration of luteinizing steroid hormone secretion may affect the development of the endometrium. It is hypothesized that correction of these underlying conditions may correct abnormal luteal phase estrogen and progesterone secretion.
Obesity
Obesity is associated with reduced fertility and an increased rate of pregnancy loss. These negative effects are particularly evident in morbid obesity. A recent study evaluated LH pulses and urinary progesterone metabolites in obese women versus normal weight controls. Altered LH pulsations (decreased pulse amplitude) were present in anorexic women, and excretion of luteal phase progesterone glucuronide (the major metabolite of progesterone) was significantly reduced in this population. It remains unclear whether this abnormality reduces reproduction rates.
Ovarian aging
Ovarian aging has also been associated with abnormal luteal phase function. Early studies showed inadequate luteal phase progesterone production, and more recent studies have shown a deficiency of metabolites of luteal phase progesterone and estrogen in women of late reproductive age. Whether these abnormalities of ovarian aging result in reduced conception rates and increased pregnancy loss is unclear.
The pathophysiology of luteal insufficiency may include several different mechanisms that ultimately affect endometrial growth. Initially ‘short luteal phase’ was described as a period of only 8 days or less between peak LH and the appearance of menstrual blood. The short luteal phase is associated with low follicular FSH levels, altered follicular FSH/LH ratio, or abnormal FSH and LH pulsations, and these follicular phase abnormalities reduce luteal estrogen and progesterone levels. However, short luteal phases may occur in young, healthy women with normal menstrual cycle lengths, so the clinical consequences of short luteal phases are currently unknown.
The luteal phase can be abnormal during in vitro fertilization cycles. Cycles with concomitant use of GnRH agonists and antagonists are associated with inadequate luteal phase hormone production.GnRH agonists may result in luteal insufficiency and low fertility attributable to prolonged suppression of pituitary LH secretion (i.e., downregulation for 3 weeks and beyond, suppression may occur. In the presence of gonadotropin-releasing hormone antagonists, conception rates are significantly lower. Although pituitary LH production resumes fairly rapidly after cessation of GnRH antagonists, clinically significant negative effects on the luteal phase may still be seen. It is hypothesized that endogenous LH may be suppressed by high gonadotropin levels during the stimulation phase. Insufficient LH stimulation of the corpus luteum may lead to reduced progesterone secretion and premature luteolysis. Interestingly, the addition of gonadotropin-releasing hormone agonists to superovulation and intrauterine insemination (SO-IUI) cycles or gonadotropin-induced ovulation (OI) cycles performed in patients with PCOS did not decrease conception rates, luteal estrogen or progesterone levels, or alter the endometrium.
Are there diagnostic criteria for luteal insufficiency?
The diagnostic test is based on several physiological features, as follows.
1. The length of the normal luteal phase is relatively fixed at 12-14 days.
2. The peak of progesterone levels in the non-pregnant cycle occurs 6-8 days after ovulation.
3. Progesterone is secreted in the form of pulses.
4.The endometrial changes reflect the follicular phase estrogen, luteal phase estrogen and progesterone.
5. Once implantation occurs, progesterone secreted by the corpus luteum is dependent on rising hCG levels.
6. The abnormal increase in hCG levels directly leads to luteal failure and decreased progesterone levels.
Several different methods have been proposed to diagnose LPD, including basal body temperature (BBT), serum progesterone levels, and endometrial biopsy. Basal body temperature measurement should be abandoned due to its inaccuracy and inconvenience to the patient.
The addition of a urine LH peak test and monitoring the length of the luteal phase confirms that ovulation and the duration of the luteal phase are normal. an interval of 11-13 days between the LH peak and menarche is considered normal, whereas an interval of 8 days or less between the LH peak and menarche is considered to be evidence of a shortened luteal phase. However, as mentioned earlier, shortened luteal phase may occur in healthy young women.
Progesterone levels
Another common method used to diagnose LPD is the measurement of serum progesterone levels. Progesterone is secreted in a pulsatile manner, reflecting the LH pulse, and its level may fluctuate up to 8 times in 90 minutes. In the unpregnant state, progesterone levels peak 6 to 8 days after ovulation. In order to determine peak progesterone levels, the timing of ovulation needs to be determined, but this in itself presents difficulties. Although the urine LH test can be used to determine ovulation, false positive peaks of LH can occur in more than 7% of menstrual cycles in women with regular menstruation.
Unfortunately, there is no standard profile of luteal phase progesterone secretion in normally fertile women. There is no minimum serum progesterone concentration to define “fertile” luteal function. In addition, luteal function varies between cycles in women of normal reproductive age. Therefore, random serum progesterone levels are not a valid clinical diagnostic tool to assess the adequacy of luteal function. Once pregnancy is established, chorionic gonadotropin stimulates the corpus luteum to produce progesterone, and progesterone levels are of some value in determining a non-viable pregnancy or an ectopic pregnancy. Low progesterone levels in early pregnancy may reflect the influence of abnormal HCG stimulation of the corpus luteum in a non-viable or ectopic pregnancy. Low progesterone levels may occur at or after the diagnosis of early pregnancy, in which case treatment should not be initiated with exogenous progesterone.
Endometrial biopsy
Abnormal endometrial maturation is considered to be the “gold standard” for the diagnosis of luteal insufficiency. Theoretically, luteal insufficiency can interfere with normal implantation or early placental development, whether the delay in endometrial maturation is due to inadequate ovarian hormone production or to an abnormality in the endometrium itself. Studies have defined that the diagnosis of luteal insufficiency depends on the traditional microscopic pattern of endometrial development during the luteal phase. However, implantation is associated with alterations in multiple factors that have not been fully explained, including steroid receptors, structural proteins, growth factors, cytokines, receptors, and implantation. Thus, the criteria defining clinically applicable normal luteal phase endometrial development are complex and ever-changing.
Many consider endometrial biopsy to be the most important diagnostic test to evaluate luteal insufficiency. However, a recent prospective double-blind randomized controlled clinical trial (RCT) has shown that endometrial biopsy is not an accurate tool to distinguish fertile women from LPD (infertile) women. In two randomized trials studying healthy fertile women with regular menstruation, up to 25% of the biopsy cycles had delayed endometrial maturation, with high variability from one cycle to the next for a given individual, and different reviews have found high histological variability. In a multicenter RCT study of 847 women with regular menstrual cycles, 49% of mid-luteal biopsies and 35% of late luteal biopsies showed “heterogeneity” and did not differ between fertile and infertile women. In conclusion, these reports confirm that endometrial biopsy for the purpose of obtaining endometrial histological manifestations is not an effective clinical diagnostic tool to identify the infertile population or to diagnose or treat LPD.
A recent study designed to test the hypothesis that low progesterone levels lead to inadequate endometrial development reached similar conclusions. In this study, GnRH agonist suppression of ovarian function was followed by two doses of intramuscularly administered progesterone on top of estradiol supplementation to compare the natural cycle profile of these two ‘patterns’ in the study population. The study showed that lowering progesterone to 3-10 ng/mL did not significantly affect the histological presentation of the endometrium.
Because histological assessment of the endometrium is inherently imprecise, many additional biochemical, morphological or molecular markers of endometrial function have been proposed to reflect when or if the endometrium is tolerant to embryo implantation. However, no tolerogenic marker is currently sufficient to distinguish infertile women from those with normal fertility. Interestingly, in the above study, endometrial protein expression appeared to differ in subjects with reduced progesterone replacement, suggesting that there may be a potentially more subtle deficiency. However, molecular markers of tolerance are still in the process of experimental studies and cannot yet be used as valid clinical diagnostic tools.
In summary, there are no reproducible, physiologically relevant clinical practice criteria to diagnose LPD and to differentiate between infertile and fertile women. The role of basal body temperature, luteal phase progesterone levels, endometrial biopsies, and other diagnostic studies has not been established and these tests cannot yet be recommended.
If the diagnosis cannot be made, is treatment appropriate?
The primary approach to treating possible luteal insufficiency is to correct all underlying abnormalities. If no underlying abnormality is identified (e.g. hypothalamic dysfunction, hypothyroidism, or hyperprolactinemia), empirical treatment is based on limited reliable data. Treatment should promote endometrial maturation, enhance endometrial tolerance and support embryo implantation and early pregnancy embryo growth. Measures include progestin, progestin plus estrogen, and human chorionic gonadotropin (hCG) supplementation during the luteal phase or after clomiphene or gonadotropin ovulation. Practice Committee guidelines can be used to guide further details.
Ovulation promotion
The use of drugs to induce ovulation improves fertility in women with low fertility. The biological mechanism for this hypothesis is based on the physiological continuity between follicular development and the corpus luteum. Improving the kinetics of the preovulatory follicle improves the function of the corpus luteum. However, two issues need to be addressed before accepting a causal relationship between the use of drugs to induce ovulation and improved luteal function and fertility outcomes. The first issue is the definition of luteal insufficiency. As needed, luteal insufficiency is defined according to alternative endpoints, such as progesterone deficiency or endometrial growth asynchrony in ovulation promotion studies. So far, all attempts to link poor fertility outcomes to these surrogate endpoints have been unsuccessful. Therefore, the only feasible way to define or diagnose LPD is to demonstrate that luteal support alone increases pregnancy and live birth rates. There have been several studies attempting to determine that ovulation-inducing drugs “treat” LPD by improving the quality or quantity of follicles. “In LPD, 18 women with asynchronous endometrial biopsies from previous clomiphene cycles were prospectively evaluated. According to the biopsy criteria, luteal insufficiency was corrected in 8/10 women who obtained more than one preovulatory follicle and in 2/8 women who obtained a single follicle. It can also be said that the “ovulation induction strategy” improves fertility by inducing multiple follicles to ovulate rather than by correcting luteal insufficiency.
Progesterone
Progesterone supplementation can be administered orally, transvaginally or by the intramuscular route. Currently, there is no evidence that progesterone is beneficial for natural unstimulated cycles. The appropriateness of progesterone supplementation in reproductive aging has not been addressed in a rigorous scientific manner.
Currently, the only well-documented indication for intravaginal or intramuscular (IM) progesterone supplementation is to improve assisted reproductive outcomes in GnRH agonist or antagonist-stimulated cycles. Intramuscular progesterone injections significantly increase serum progesterone levels while intravaginal progesterone use increases endometrial tissue progesterone levels. Studies have concluded that oral progestins should not be used for luteal support because only about 10% of micronized progesterone is absorbed intact through the gastrointestinal tract, and ART cycles with oral administration have low pregnancy rates compared with vaginal administration or intramuscular injection. Progesterone supplementation should be continued until after adequate placental progesterone production at 8-10 weeks of gestation.
Human chorionic gonadotropin-hCG
Luteal supplementation with chorionic gonadotropin during ART cycles with GnRH agonists/antagonists stimulates ovarian (or corpus luteum) production of endogenous progesterone and estrogen. In ART cycles with GnRH agonists/antagonists, hCG supplementation has a higher delivery rate and a lower spontaneous abortion rate than no supplementation. However, the incidence of moderate or severe ovarian hyperstimulation (OHSS) was significantly higher with hCG supplementation. Low doses of hCG (500 IU every other day) provide luteal support and have a low risk of inducing ovarian hyperstimulation syndrome. Progesterone is preferred in GnRH agonist/antagonist IVF cycles because of the clinical equivalence but higher incidence of side effects with hCG and intramuscular progesterone. Once pregnancy is established, there is no benefit to hCG supplementation. A randomized controlled trial of hCG supplementation found an 11% miscarriage rate in the placebo group compared to 12% in the hCG supplementation group in 183 women with vaginal bleeding in early pregnancy and ultrasound-confirmed fetal heart activity.
In conclusion
Medical conditions may cause abnormal luteal function (e.g., elevated prolactin, abnormal thyroid function), and infertile women should be screened for these conditions and treated appropriately. There are no clinically reliable diagnostic tests for luteal insufficiency. The role of basal body temperature, luteal phase progesterone levels, endometrial biopsies, and other diagnostic studies has not been established and testing for these tests is not recommended. Treatment of luteal insufficiency does not improve pregnancy outcomes in natural, unstimulated cycles.
Luteal support with progesterone or hCG after ART improves pregnancy outcomes, but chorionic gonadotropin increases the risk of ovarian hyperstimulation syndrome.
The role of luteal support with progesterone or hCG given immediately after confirmation of pregnancy is unclear. No benefit of progesterone supplementation beyond the expected time of menarche (i.e., 2 weeks after ovulation) in non-ART cycles is currently confirmed.
Conclusion
Although progesterone plays an important role in the embryo implantation process and early embryonic development, LPD has not been proven to be an independent factor in infertility.