Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, Delhi, 110029, India
Controlled ovarian stimulation is a determining factor in the success of ART cycles. Clinics the world over use ultrasound and endocrine hormone assessment to monitor these cycles to optimize success by getting the ideal number of oocytes and therefore good embryos. Further monitoring helps avert complications of hyperstimulation besides a poor response. The commonly indicated hormone assays for monitoring cycles include oestradiol, luteinizing hormone and lately progesterone. Endocrine monitoring is combined with ultrasound tracking; even though the role of intensive monitoring combining the two is controversial, it is recommended as ultrasound with serum oestradiol is utilized as a precautionary good practice.
HormoneAssaysLuteinizing hormoneEstradiolProgesteroneMonitoringART cycles
Assisted reproductive techniques (ARTs) have been declared a major medical breakthrough ever since the birth of the first in vitro fertilization (IVF) baby in 1978. By the end of 2013, approximately five million babies have been born worldwide from ART techniques including IVF and intra-cytoplasmic sperm injection (ICSI) . While the first IVF baby was the outcome of a natural cycle, a remarkable increase in IVF success has been attributed to effective controlled ovarian hyperstimulation (COH). COH is apparently a key factor in the success of in vitro fertilization-embryo transfer (IVF-ET) and essentially involves programming ovarian stimulation and monitoring of cycles. The aim of COH in ART cycles is to procure as many mature oocytes, with better chance of good embryos that can be transferred and the spare ones frozen for future use, increasing the cumulative pregnancy rate. While monitoring ovulation induction gives us an idea of how long to go, essentially in ART cycles where the number of embryos transferred can be restricted reducing the risk of multiples, the risk of ovarian hyperstimulation syndrome (OHSS) or poor response is a prime concern of clinicians such that the cycle culminates in a successful embryo transfer.
What is the need to monitor cycles? Essentially monitoring during ART cycles is for
Monitoring is therefore essential before the start of COH to identify poor responders as well as those likely to hyperstimulate . Of the methods described to monitor ART cycles, ultrasound imaging of the utero-ovarian response to gonadotropins is clinically most relevant. However used alone, it was realized that the mean size and the volume of the developing follicles seemed to vary greatly . This combined with hormone analysis mainly oestradiol levels is most commonly utilized in clinics the world over. Hormonal control of ovarian activity by gonadotropins plays an important role in folliculogenesis. Besides gonadotropins, steroid hormones are also key players and are usefully measured in monitoring ART cycles. While gonadotropin assays do not adequately reflect the biological activity of gonadotropins, the endocrine characteristics of COH cycles can be assessed by steroids, including oestradiol and progesterone, as they reflect the biological activity of the gonadotropins on the ovary. Also steroids have an effect on implantation process and may play a paracrine and autocrine role on the cumulus complex.
In this chapter we see how the currently used pharmacologic agents (GnRH analogues, gonadotropins) modify the endocrine milieu and how useful are their measurements in cycle monitoring in terms of control and prediction of outcome.
19.2 Gonadotropin Analysis During Controlled Ovarian Hyperstimulation
Over the years with availability of assisted reproductive techniques, using GnRH analogues has given a better understanding of the role of follicular stimulating hormone (FSH) and leutinizing hormone (LH) in folliculogenesis. According to the two cell-two gonadotropin theory , both FSH and LH are important for follicular growth and development. The role of either of them in cycle control is discussed.
19.2.1 Follicle Stimulating Hormone (FSH)
During the follicular phase of cycle, FSH is involved in recruitment, selection and dominance of follicle. It is involved in the recruitment of the cohort at an early follicular phase and stimulates the transcription of genes within the granulosa cells, initiating the synthesis of aromatase enzyme, inhibins and LH receptors that are involved in follicle differentiation and growth .
A certain amount of FSH secretion - ‘FSH threshold ‘ is required to induce follicle growth, and as this threshold is not identical for follicles even of the same cohort, the FSH dose for inducing multi-follicular development should cross the threshold of the least sensitive follicles. Thus the endogenous FSH is crucial to the cycle in inducing follicular recruitment. The other aspect of ‘FSH window’ is also crucial as this means that follicular growth is maintained as long as the FSH levels are above the threshold for the follicle. While in natural cycle the progressive decline in FSH secretion due to the feedback effect of ovarian hormones on the pituitary leads to dominance of a selected follicle and atresia of others, during COH the FSH levels are above the threshold and the window that remains open until the final stage of follicular development resulting in multiple follicles at the time of trigger. Thus FSH is the main therapeutic drug that controls the folliculogenesis in all cases except hypogonadotropic hypogonadism where LH supplementation is necessary for production of steroid hormones.
During COH both gonadotropins and GnRH analogue are used to attain multi-follicular development, but the effects of each on the levels of FSH are variable. With gonadotropins there is a plateau of plasma FSH levels due to the long elimination half-life of FSH molecules (30–35 h). This FSH accumulation lasts for 5 days, and despite cessation of exogenous FSH administration follicles continue to mature. Also plasma levels of FSH after an intramuscular or subcutaneous dose cause a transient (4–8 h) and modest rise in plasma FSH levels, which are further not reflective of the actual bioactivity of the molecule. For these reasons there appears little justification in measuring FSH levels to adjust FSH doses or to establish the threshold above which ovarian response can be observed. This was further supported by a study by Van Weissanbrunch et al., who measured serial FSH levels to determine the adequate threshold FSH dose . FSH was administered in a pulsatile manner to adjust the daily requirement according to the plasma FSH levels. The study found poor correlation between plasma FSH levels and the FSH threshold, as there was an overlap of plasma FSH levels between the groups of patients who demonstrated follicular recruitment as against those who did not .
The effects of agonist on FSH levels depend on the preparation and duration of use. There is an initial rise or flare effect of agonist at the pituitary resulting in a significant rise in plasma FSH levels with resultant recruitment that is exploited in a short protocol. The amplitude of FSH response to GnRH-agonist is lower than LH , and the desensitizing effect of prolonged GnRH-a administration on FSH secretion is much less than LH [8, 9]. Further FSH bioactivity may not decrease during GnRH-a administration . Therefore, measuring plasma FSH is unlikely to be of benefit in the course GnRH-a therapy. Even in antagonist cycle, the gonadotroph suppression was less marked for FSH than for LH as suggested in studies available . Summing up from available evidence on FSH variations during ART treatment, there seems to be no contribution of FSH estimation in deciding gonadotropin doses or regimen in clinical practice.
19.2.2 Luteinizing Hormone (LH)
Luteinizing hormone acts on the theca cells while producing androgens throughout the follicular phase. Androgens are the substrate for the production of oestradiol (E2) by granulosa cells. LH induces a dose-dependent production of E2, and this is foremost in endometrial preparation for embryo implantation . There is a minimal amount of LH, described as the ‘LH threshold’, required for pregnancy; however, higher levels are detrimental with a negative impact on endometrium rather than on oocytes/embryos [13, 14]. Using high doses of LH has a negative influence on follicular development, a concept of ‘LH ceiling’ , wherein LH beyond a certain level suppresses granulosa cell proliferation and results in atresia of less mature follicles (11–15 mm) . Substitution of LH in the later follicular phase with recombinant LH alone is known to cause reduction in size and number of large follicles as seen in both type I and type II WHO anovulation category of women . LH therefore synergizes with FSH during the whole follicular phase of folliculogenesis.
As regards LH in ART cycles, urinary human menopausal gonadotropin (hMG) commonly used in earlier years contains LH, and this is cleared rapidly from circulation owing to a short half-life  approximately 12 h as compared to 30 h for FSH. Therefore there is little evidence of accumulation following hMG injection. The use of agonist in ART cycles is known for the initial flare effect, as used in ultra-short and short protocols where rise promotes early follicular recruitment. The endogenous FSH and LH rise within 24 h of GnRH agonist administration, the flare effect being more marked for LH than FSH . This subsequently stimulates secretion of E2, which is considered a predictor of ovarian response to gonadotropins. Thus estimation of LH does not reflect adequacy of flare-up response.
Measurement of plasma LH is routinely done to confirm pituitary desensitization and confirm adequate down-regulation after long-term administration of GnRH agonist. Adequate down-regulation is suggested by LH levels <3 IU/L. The rate and extent of LH suppression is dependent on the type of agonist, its route and dose used . As long as the GnRH-a is given, the hypophysis is refractory to endogenous GnRH and there are no pulsatile LH secretions. The extent of LH suppression is variable after desensitization as when there are profound falls in LH levels higher doses of gonadotropins are needed to achieve ovarian stimulation. Thus in GnRH agonist-based cycles, levels of LH may have a bearing on ART outcome. The endogenous LH levels are within the normal limits (1–4 IU/L) or are within the limits defined by LH ceiling and LH threshold as sufficient for steroidogenesis and folliculogenesis.
Though low LH levels are associated with little difference in birth rate, women with LH levels less than 1.2 IU/L require higher doses of gonadotropins during ovarian stimulation . Thus in poor responders lower doses of GnRH-a are suggested for adequate response to gonadotropins. In keeping with the two-cell–two-gonadotropin theory, administration of pure or recombinant FSH should not be sufficient to stimulate E2 production. However, results from large studies suggest that FSH administration is sufficient to obtain adequate number of good-quality oocytes and embryos with high implantation rate, as there is still endogenous LH, despite profound down-regulation when LH levels are measured to be low . Later studies evaluated outcome in ART cycles according to the plasma levels of LH at the time of desensitization or later in mid-follicular phase [21, 22]. Those patients with LH levels <0.5 IU/L had reduced E2 concentrations at the time of hCG trigger and lower number of oocytes and embryos when stimulated with FSH alone. However, the rate of blastocyst development was unaffected. Thus measurement of LH during the cycle fails to define a sub-group of women who would need additional LH to achieve ovarian stimulation. Therefore, the threshold of LH below which folliculogenesis may be impaired cannot be assessed by measuring LH after down-regulation. There is however no relation between endogenous LH levels and ovarian response, implantation rate and pregnancy rate when normogonadotropic women undergo IVF cycles as suggested by a later meta-analysis .
19.3 Steroid Hormone Profile During COH
Steroid hormone estimations including oestradiol and progesterone are routine parts of hormone monitoring of ART cycles. Plasma E2 levels are a good indicator of granulosa cell differentiation and are useful in evaluating follicular maturity. Plasma progesterone (P) is useful in assessing premature luteinization, though with the use of GnRH analogues this should be uncommon. Plasma androgen are rarely performed clinically in monitoring ART cycles.
19.3.1 Oestradiol (E2)
Plasma E2 levels are useful in assessing follicular maturity as the synthesis of E2 associates with dominant follicles in natural cycles. During ART cycles plasma E2 levels are performed combined with ultrasound to adjust doses of gonadotropins. E2 synthesis is related to follicle size, and a mature follicle has an output of approximately 200 pg/ml. In days before the use of GnRH analogues to prevent endogenous LH surge, serial E2 levels were estimated as they correlated well with cycle outcome . With the availability of GnRH-a protocols the problem of premature LH surges is taken care of, but the estimations of E2 are still recommended to confirm pituitary desensitization. After effective desensitization plasma E2 levels must be lower than 50 pg/ml, that is, after 2 weeks of GnRH-a, when the initiation of gonadotropins for ovarian stimulation can be given. While plasma LH levels are also estimated to confirm desensitization, they cannot adequately reflect the same for reasons discussed in previous sections. Mid-luteal start of GnRH-a and use of long-acting preparations of agonist are associated with profound and immediate desensitization [25, 26]. Whether the prompt desensitization is associated with ovarian refractoriness and the need for higher doses of gonadotropins is debatable ; ovarian stimulation with FSH alone should be initiated only once ovarian activity is suppressed. During the ovarian stimulation, levels of E2 guide in determining the optimal response. Plasma E2 levels closely follow stages of development of growing follicles. After 6 days of gonadotropins, an increase in plasma E2 levels is defined as optimal response; however, due to extreme diversity of protocols, the ideal levels of E2 are not defined. A plateau in plasma E2 for more than 3 days suggests poor response to gonadotropins. Conversely excessive response can be gauged by an exponential rise in E2, which helps decide coasting or cancellation. An E2 window of 1,000–1,500 pg/ml is optimal once follicles reach 15 mm . The risk of hyperstimulation is significant with levels more than 3,000 pg/ml . Therefore, E2 monitoring is relevant and should be a part to define optimal response, even though some studies suggest that ultrasound monitoring is sufficient to make decisions during stimulation .
Further in antagonist protocols the pattern of E2 during stimulation differs from that in agonist protocols. Plasma E2 levels are higher before the addition of GnRH antagonist, and after the addition of antagonist to control the LH surge, the E2 levels may rise moderately, remain the same or even decline . But these variations in E2 levels do not compromise the cycle outcome. Unlike agonist cycle E2 levels are of little help in adjusting gonadotropin doses after the antagonist has been added to cycle.
The levels of E2 have an important bearing on day of hCG trigger. A value more than 200 pg/ml per dominant follicle suggests adequate response and should be correlated with follicle monitoring on ultrasound. Despite a debatable role of E2 in pathogenesis of OHSS, E2 assessment is an important marker to predict women at risk of OHSS. The relationship between E2 levels and OHSS is controversial . Absolute levels and rate of rise in E2 levels have been described to predict OHSS; however, no value is shown to be an independent predictor . In general, the risk of OHSS is felt to increase variably with E2 levels >3,000–4,000 pg/mL [27, 28]. Papanikolaou and colleagues have shown that if a threshold of 3,000 pg/ml had been used, only a third of the total OHSS cases would have been predicted. Because severe cases are the more clinically significant, only 37.0 % of them would have been predicted (specificity 87 %) . Using ROC curves, a cut-off value of 2,560 ng/L could not predict more than half of the severe cases (49 % sensitivity; 77 % specificity) . There is no clear cut-off limit of E2 levels that predicts the risk and severity of the syndrome. Although Asch and colleagues showed that values >6,000 pg/mL in IVF cycles were associated with a severe OHSS rate of 38 %, others reported an 8.8 % rate with the same cut-off [34, 35]. These observations actually suggest that considering only high E2 levels as a risk factor is unreliable for the prediction of OHSS. While absolute values have poor predictive value for OHSS, the combination of E2 and follicle measurement produces a criterion as given in a study by Paanikolaou et al. . More than 18 dominant follicles and/or E2 of 5,000 pg/L had a significant positive likelihood ratio (LR = 5.19) that can predict 83 % of the severe OHSS cases, including both early and late cases, with an acceptable specificity of 84 % . A level less than 3,000 pg/ml is safe for hCG trigger.
Coasting may be a method to avert OHSS wherein levels of E2 are lowered to safe levels by withholding gonadotropins and reducing the risk of severe OHSS . At what levels of E2 should coasting be initiated is debatable. Some investigators consider that an E2 level >3,000 pg/mL is enough to start coasting [35, 36], while another group only initiate coasting if the E2 level is >6,000 pg/mL . Garcia-Velasco recommend initiating coasting when >15–20 follicles >16 mm are detected by trans-vaginal ultrasound, and serum E2 levels are >4,500 pg/mL on the day that hCG triggers . The role of serial oestradiol estimation once coasting is initiated is paramount. The serum E2 level is evaluated on a daily basis because serum E2 behaviour is erratic and sudden unexpected drops might occur, which usually are associated with a marked decrease in oocyte quality and a lower pregnancy rate . The decline in E2 is estimated to begin on an average 1.7 days of coasting  and as soon as the levels drop to <3,500 pg/mL, either 5,000 IU of urinary hCG or 6,500 IU of recombinant hCG are given, egg retrieval is scheduled and the cycle continues as planned.
Besides the risk of OHSS, and role of E2 during coasting, high levels of E2 have a negative impact on endometrial receptivity . This deleterious effect on endometrial receptivity is seen in high responders with E2 levels above the 75th percentile (>2,446 pg/ml), an improved embryo quality without a concomitant rise in pregnancy rate .
Prior to the availability of GnRH agonist, detection of premature LH surges was mandatory as these LH surges were associated with high rates of fertilization failure. Measurement of progesterone was used as a surrogate test to detect partial luteinization of granulosa cells as short surges could not be detected by daily LH monitoring. With the use of GnRH agonist and antagonist in varying protocols to prevent LH surges the need to monitor with progesterone is limited. However there are situations when progesterone is a useful hormonal tool to monitor COH.
Measurements of progesterone at the time of down-regulation are of value as they indicate that corpus luteum is inactive and not inadvertently rescued by GnRH agonist flare-up or uncommonly by a spontaneous pregnancy. After mid-luteal start of GnRH-a, the formation of cysts is associated with rise in progesterone levels and justifies the puncture of such cysts before starting FSH. Since the rise in progesterone could have deleterious effects on ovary and endometrium, it is to be ensured that ovarian stimulation should not be started in a hormonal environment that is hostile to the ovary and endometrium. Extending the administration of GnRH agonist or postponing ovarian stimulation is the best strategy. It is recommended that plasma P levels be measured even before an antagonist cycle and ovarian stimulation should be postponed with levels >1.4 ngm/ml .
During the latter part of ovarian stimulation measurements of progesterone are considered to indicate premature luteinization. However it is not uncommon to find this progesterone rise, as in 5–35 % of stimulated cycles it may be associated without a concomitant rise in LH levels. In such situations a rise in P cannot be considered a premature luteinization. There are several questions as to what is the mechanism of this rise in P levels. Indeed rising progesterone could be the consequence of higher production from granulosa cells in response to high doses of FSH or may be considered as an early expression of occult ovarian failure . This may perhaps be one of the reasons why lower doses of FSH improve pregnancy rate, perhaps by lowering levels of progesterone during follicular growth in ART cycle. The high levels of progesterone on the day of hCG may have a negative effect on the pregnancy rates.
The Menotropin Versus Recombinant FSH In Vitro Fertilization trial (merit) study compared stimulation with highly purified human menopausal gonadotropin or recombinant FSH following a long GnRH-agonist protocol [43, 44]. The critical value for defining elevated progesterone in the study was 4 nmol/L on the day of hCG trigger. The serum progesterone was higher in r-FHS-treated patients with the resultant lower implantation rate as compared to patients treated with HP-hMG. Bosch et al. in a subsequent study reported that high serum progesterone concentration on the day of hCG (>1.5 ng/per ml or 4.77 nmol/L) was associated with a decreased pregnancy rate . These findings suggest that a pre-hCG rise in progesterone may be responsible in advancement of endometrial maturation, leading to asynchrony with embryo development and negative impact on implantation .
Elgindy in a prospective study correlated progesterone/oestradiol (P: E) ratio on the hCG to pregnancy rates . Using ROC curves a cut of 1.5 ng/ml and 0.55 were defined for P and P/E ratio respectively. Patients with P less than 1.5 ng/ml and P/E less than 0.55 undergoing cleavage stage embryo transfers had higher clinical pregnancy rates. Theses cut-offs did not correlate with pregnancy rates after blastocyst transfer. This study highlighted that the detrimental effects of progesterone on pregnancy outcome are attributed to temporarily defected endometrial receptivity that recovers a few days later. There was a distinct difference in endometrial gene expression with a progesterone concentration above or below the threshold of 1.5 ng/ml on the day of hCG administration . It seems that progesterone rise (>1.5 ng/ml or 4.77 nmol/l) affects endometrial receptivity by accelerating the endometrial maturation process that narrows the implantation window thereby decreasing pregnancy rates.
However, a meta-analysis by Venetis et al. found no difference in pregnancy rates with raised follicular phase progesterone . However, the flaw in this meta-analysis was that it did not take into account the different threshold values of progesterone used in these studies. A retrospective study assessed the impact of P and P/E on the day of hCG in agonist cycle and concluded that there was no difference in pregnancy rate between patients with elevated P and P/E ratio as compared to those with normal range indicating these hormone assays are of limited value in decision to cryopreserve embryo or go ahead with fresh transfer .
19.4 Ultrasound Versus Endocrine Monitoring of ART Cycles
The gold standard for IVF monitoring includes both trans-vaginal ultrasound and E2 monitoring. Though ovarian stimulation is monitored in ART cycles with serial measurements of estradiol and ultrasound monitoring, results comparing cycles monitored with or without hormonal estimations as adjunct to ultrasound do not support superiority of combined monitoring. Murad in a study concluded that ultrasound only monitoring was cheaper, less time consuming, and more convenient for both patients and the team when compared to hormonal and ultrasound monitoring of IVF cycles .
Lass in a multicenter, prospective randomized trial from UK did not show any benefit of additional E2 estimation over ultrasound only monitoring in terms of pregnancy rate, decision to time hCG trigger or risk of OHSS . Further, although a systematic review did not show that E2 monitoring prevented OHSS, it did conclude that E2 monitoring should continue to be routinely performed as a ‘precautionary good practice point’ . While E2 alone was used in the earlier years of IVF, additional hormone assays have a disadvantage of frequent blood sampling, the need for a reliable laboratory setup and costs involved. While units worldwide are involved in developing stimulation protocols that minimize monitoring and therefore costs to the patient, use of minimal hormone analysis as in minimal oestradiol estimations with ultrasound monitoring of cycle is likely to stay.
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