Department of Obstetrics and Gynaecology, Manipal Assisted Reproduction Centre, Kasturba Medical College, Manipal University, Manipal, Karnataka, 576104, India
The ideal ovarian stimulation regimen for IVF should have a low cancelation rate, minimize drug costs, have low risks and side effects, require limited monitoring for practical convenience, and maximize singleton pregnancy rates. Individualization starts from an assessment before the start of IVF cycle of the ovarian reserve by antral follicle count (AFC), antimullerian hormone (AMH), FSH, and age of the patient. AFC and AMH are the most sensitive markers of ovarian reserve identified to date and should be used to plan individualized treatment. Once the patient is categorized as a hypo-/hyper- or normoresponder the dose of gonadotropin is decided. The selection of dose is of paramount importance for optimal outcome of controlled ovarian stimulation (COS). In case of poor responders and hyper-responders, GnRH antagonist regimes are preferred. This helps in explaining the prognosis and in appropriate counseling and also ensures a safe controlled ovarian stimulation with optimal results which prevent unnecessary psychological and financial burden on the couple. Cycle monitoring is important to decide any alteration in dose or when to add GnRH antagonist. In women at high risk for ovarian stimulation, it is important to start with low doses and intensive monitoring. In case there are indications of hyperstimulation, the regime may be altered by decreasing dose or coasting. Many factors are interdependent, and hence, a careful selection of the type of ovarian stimulation will be the key factor in deciding the success of the same.
The ideal ovarian stimulation regimen for IVF should have a low cancelation rate, minimize drug costs, have low risks and side effects, require limited monitoring for practical convenience, and maximize singleton pregnancy rates, but this regimen has not yet been defined. It should be tailored according to the patient’s characteristics. Numerous regimens have been described, ranging from no stimulation (natural cycles) to minimal stimulation (clomiphene citrate) or mild stimulation to aggressive stimulation (high dose exogenous gonadotropins) alone or in combination with a gonadotropin-releasing hormone (GnRH) agonist or antagonist. Each has its advantages, disadvantages, and applications. The stimulation regimen selected for any one individual should be based on age, response to any previous stimulation, and ovarian reserve. This would predict response and help individualize the drug regime which is to be followed. Individualization would be needed to decide the gonadotropin type and dose as well as whether an agonist or antagonist is to be used for suppression of LH. It is important to individualize to prevent hyper-response or poor response, improve results, and prevent unnecessary psychological and financial burden on the couple.
13.2 Evaluation Before IVF to Individualize Ovarian Stimulation
The following are recommended to decide on the dosage and the type of stimulation.
13.2.1 Ovarian Reserve
Ovarian reserve testing has prognostic value and is recommended for all women planning assisted reproductive technology (ART). Because ovarian response is inversely related to the day 3 serum FSH level, results of FSH may help to guide the choice among treatment regimens and the dose of gonadotropins to be used for stimulation. However, estimating the antimullerian hormone (AMH) levels will also give an idea about the response.
La Marca reported the AMH level of 0.7 ng/ml had a good sensitivity and specificity of identifying 75 % of poor responders . AMH of >3.5 ng/ml predicted hyper-response and OHSS. AMH levels are higher in PCOS . Eldar-Geva et al. reported an additional increase in AMH levels were observed in PCOS patients due to abnormal activity of granulosa cells, hyperandrogenism, and obesity . Hence, the dosage should be monitored for ovulation induction depending upon the AMH values. The dosage is more for a lesser value and less for a higher value. In PCOS the dosage may start with 112.5/150 IU, whereas in a woman with lower reserve, it can be as high as 600 IU.
Antral follicle count on days 2–3 of the cycle gives a good estimate of the number of eggs to be obtained by ovarian stimulation. Each ovary having about six to eight antral follicles seems to be a good responder.
AFC and AMH are the most sensitive markers of ovarian reserve identified to date and should be used to plan individualized treatment. It has been suggested by a recent review that either of the two markers can be used as they have equal accuracy in prediction of response . So once the patient is categorized as a hypo-/hyper- or normoresponder, the dose of gonadotropin is decided. The selection of dose is of paramount importance for optimal outcome of COS. Also in case of poor responders and hyper-responders, GnRH antagonist regimes are preferred. This helps in explaining the prognosis and in appropriate counseling and also ensures a safe controlled ovarian stimulation with optimal results.
13.2.2 Age of the Woman
Age is an important factor in fertility, and chances of conception decrease with advancing years, usually after the 30s. The reason why fertility decreases with increasing age is the diminished number of eggs left in the ovary. Unlike men, who produce new sperm daily throughout most of their lifetime, women are born with all their eggs in two ovaries. To be more precise, a woman is born with about one to two million immature eggs, or follicles, in her ovaries.
Throughout her life, the vast majority of follicles will die through a process known as atresia. Atresia begins at birth and continues throughout the course of the woman’s reproductive life. When a woman reaches puberty and starts to menstruate, only about 400,000 follicles remain. With each menstrual cycle, 1,000 follicles are lost and only 1 follicle will actually mature into an ovum (egg), which is released into the fallopian tube, kicking off ovulation. That means that of the one to two million follicles, only about 400 will ever mature.
Relatively little or no follicles remain at menopause, which usually begins when a woman is between 48 and 55 years of age. The remaining follicles are unlikely to mature and become viable eggs because of the hormonal changes that come along with menopause.
Most infertility specialists define an older woman as one who is more than 35 years, but this is an arbitrary number. A woman’s fertility does not fall at a particular age, but starts declining gradually after the age of 30. After 35, the drop is fairly dramatic; and after 38, it’s even more so. However, there is no magic number at which fertility disappears, and this decline is a progressive irreversible process.
In the past, it was assumed that as the woman got older, her entire reproductive system started failing. However, today we know that the uterus and the fallopian tubes remain relatively unaffected by age and that the reason for the decline in fertility is the diminished number of eggs left in the ovary. The infertility specialist is really not interested in the woman’s calendar (or chronological age), but rather her biological age – or how many eggs are left in her ovaries.
13.2.3 Weight and BMI
Women having a normal BMI have maximum oocyte retrieval, fertilization, implantation, and clinical pregnancy rates in comparison to obese females .
In a recent study it was found that increased doses of gonadotropins were required with increase in patient’s BMI. No difference was seen in the number of oocyte retrieved, but a decreased fertilization and cleavage rate was seen with decreased number of cryopreserved embryos with increasing BMI. This study shows that poorer oocyte quality is seen with increasing BMI which results in reduced clinical pregnancy rate . Hence, these women should be started at higher doses.
The CONSORT study developed a dosing algorithm which individualizes recombinant human FSH (r-hFSH) doses for assisted reproductive technologies, assigning 37.5 IU increments according to patient characteristics: basal FSH, body mass index, age, and antral follicle count .
13.3 Individualizing Protocols for Prevention of Premature LH Surge
13.3.1 Exogenous Gonadotropin Stimulation After Downregulation with a Long-Acting GnRH Agonist: Long Protocols
The introduction of long-acting GnRH agonists in the late 1980s revolutionized the approach to ovarian stimulation in ART by providing the means to downregulate endogenous pituitary gonadotropin secretion and thereby prevent a premature LH surge during exogenous gonadotropin stimulation. Adjuvant treatment with a GnRH agonist eliminated the need for frequent serum LH measurements and assuaged fears of premature luteinization which previously had necessitated cancelation of approximately 20 % of all IVF cycles before oocyte retrieval. Because fewer than 2 % of cycles are complicated by a premature LH surge after downregulation with a GnRH agonist, stimulation could continue until follicles were larger and more mature. Clinical trials subsequently demonstrated that oocyte yields and pregnancy rates were significantly higher than in cycles stimulated with exogenous gonadotropins alone . Moreover, GnRH agonist treatment offered the welcome additional advantage of scheduling flexibility, allowing programs to coordinate cycle starts for groups of women simply by varying the duration of GnRH agonist suppression. Not surprisingly, the long protocol quickly became the preferred ovarian stimulation regimen for all forms of ART.
GnRH agonist treatment sometimes blunts the response to subsequent gonadotropin stimulation and increases the dose and duration of gonadotropin therapy required to stimulate follicular development. However, with poor ovarian reserve this is not the preferred protocol. The combined costs of the additional gonadotropins and the agonist itself increase the total cost of treatment.
Gonadotropin stimulation also yields more follicles and oocytes when agonist treatment begins during the luteal phase, possibly because LH-stimulated androgen production and circulating androgen levels are more effectively suppressed throughout folliculogenesis. Because the egg yield is greater, the number of embryos available is also increased. Consequently, the probability of having an optimal number of embryos for transfer and excess embryos for cryopreservation is greater. GnRH agonist treatment may be scheduled to begin on cycle day 21 (assuming a normal cycle of approximately 28 days of duration). Hence, in a woman with polycystic ovary syndrome (PCOS), a long protocol may be useful to reduce the LH levels and have a better oocyte recovery and ongoing pregnancy rates.
Overall, the weight of available evidence suggests that women who require longer durations of GnRH agonist treatment to achieve suppression or who develop cysts are more likely to respond poorly to gonadotropin stimulation; those who do are understandably less likely to succeed. The initial dose of exogenous gonadotropins used to stimulate ovarian follicular development after GnRH agonist-induced downregulation should be tailored to the needs of the individual woman. Typical starting doses range between 225 and 300 IU of urinary FSH (uFSH), recombinant FSH (rFSH), or urinary menotropins (hMG) daily, depending on the age, the results of ovarian reserve testing, and the response observed in any previous superovulation or IVF cycles. Either a “step-up” (beginning with a low dose, increasing as necessary based on response) or “step-down” (beginning with a higher dose, decreasing as necessary based on response) may be used, but the latter approach is generally preferred.
Concerns persist that GnRH agonist treatment may suppress endogenous LH levels below those necessary for normal follicular development in at least some women. Because only about 1 % of LH receptors must be occupied to support normal follicular steroidogenesis, the low levels of LH secretion after downregulation with a GnRH agonist are sufficient to meet the need in most women stimulated with uFSH or rFSH alone. However, LH concentrations also may be inadequate in those who are more profoundly suppressed. Indeed, LH levels are markedly suppressed (less than 1 IU/L) in many who are treated only with FSH, and in such cycles, the dose and duration of gonadotropins required are higher and peak estradiol levels are lower; the number of oocytes and embryos may also be reduced. Another evidence suggests that fertilization, implantation, and pregnancy rates may be adversely affected when LH levels are extremely low . The evidence indicates that there may be a subgroup of eugonadotropic women that could benefit from supplemental hMG or rLH during ovarian stimulation.
13.3.2 Stimulation with Exogenous Gonadotropins with Addition of a GnRH Antagonist
The relatively recent introduction of GnRH antagonists into clinical practice has provided another option for ovarian stimulation in ART. GnRH antagonists, being more complex than agonists, act through a completely different mechanism for inhibiting gonadotropin secretion. GnRH antagonists bind competitively to GnRH receptors preventing the action of endogenous GnRH pulses on the pituitary. Not only the secretion of gonadotropins is decreased within hours of antagonist administration, but in addition no flare-up effect occurs. Moreover discontinuation of GnRH antagonist treatment results in rapid and predictable recovery of the pituitary-gonadal axis as the pituitary receptor system remains intact.
In contrast to the agonists, antagonist treatment is highly dose dependant, relying on the balance between endogenous GnRH present and antagonist administered. Most importantly, within 6–8 h of administration, any imminent LH surge is blocked. The first generation of GnRH antagonists, besides binding to pituitary receptors, could in addition bind to GnRH receptors in mast cells resulting in degranulation and histamine release, consequences that impeded their use in assisted reproductive technologies for almost a decade. Thus, until some time back, downregulation in IVF was accomplished almost exclusively with the use of GnRH agonists.
18.104.22.168 Advantages of GnRH Antagonists
· The duration of treatment for an antagonist is substantially shorter than for an agonist.
· Since its only purpose is to prevent a premature endogenous LH surge and its effects are immediate, antagonist treatment can be postponed until later in follicular development (after 5–7 days of gonadotropin stimulation), after estradiol levels are already elevated, thereby eliminating the estrogen deficiency symptoms that can emerge in women treated with an agonist.
· Because any suppressive effects that agonists may exert on the ovarian response to gonadotropin stimulation are also eliminated, the total dose and duration of gonadotropin stimulation required may be decreased.
· By eliminating the flare effect of agonists, GnRH antagonists avoid the risk of stimulating development of a follicular cyst.
· The risk of severe ovarian hyperstimulation associated with the use of antagonists appears lower than with agonists.
22.214.171.124 Disadvantages of GnRH Antagonists
· When administered in small daily doses, strict compliance with the prescribed treatment regimen is essential.
· Low levels of LH observed during agonist treatment are usually sufficient to support normal follicular steroidogenesis when uFSH or rFSH is used for stimulation; the even lower concentrations in women treated with an antagonist may not be sufficient however.
· There is evidence to suggest that pregnancy rates in antagonist treatment cycles may be modestly lower than in cycles using agonists in the long protocol, possibly because GnRH antagonists may influence the mitotic programming of cells involved in folliculogenesis, blastomere formation, and endometrial development.
The two GnRH antagonists available for clinical use are equally potent and effective. For both, the minimum effective dose to prevent premature LH surge is 0.25 mg daily, administered subcutaneously . Either of the antagonists can be administered in a series of small daily doses (0.25 mg). The treatment protocol can be fixed to begin after 5–6 days of gonadotropin stimulation or tailored to the response of the individual, starting treatment when the lead follicle reaches approximately 13–14 mm in diameter. Alternatively, a single larger dose of cetrorelix (3.0 mg) will effectively prevent an LH surge for 96 h. If given on days 6–7 of stimulation, the interval of effective suppression will encompass the day of hCG administration in most women (75–90 %); the remainder may receive additional daily doses (0.25 mg) as needed, ending on the day of hCG treatment. The single-dose antagonist treatment regimen also may be withheld until the lead follicle reaches 13–14 mm in diameter .
ART stimulation regimens are still uncertain, but antagonists have been viewed as holding particular promise for women with polycystic ovary syndrome and those who respond poorly to stimulation after treatment with an agonist. The antagonist treatment regimens currently in use also have potential disadvantages for women with polycystic ovary syndrome. Their tonically elevated LH levels will remain high until antagonist treatment begins. Consequently, LH levels can rise prematurely, particularly if antagonist treatment is withheld until the lead follicle reaches 14 mm or more. Moreover, evidence indicates that increased LH exposure during early follicular development may be detrimental and predispose to lower pregnancy rates.
In theory, pretreatment with an oral contraceptive might prove quite useful by suppressing LH and androgen levels before stimulation begins, decreasing exposure during early follicular development and the risk of rising LH levels before antagonist treatment begins. Preliminary oral contraceptive suppression and later antagonist treatment may also help to limit the follicular response to gonadotropin stimulation while preserving the option to use an agonist to trigger final oocyte maturation. An earlier start to antagonist treatment may offer similar advantages. These and other considerations simply serve to illustrate that GnRH antagonists are not a panacea and may not even be the best choice for women with polycystic ovary syndrome.
Poor responders are another group for which GnRH antagonists may have particular value because antagonist treatment eliminates any suppressive effects that the long-acting agonists may have on follicular response and can prevent the premature LH surges commonly observed in women stimulated with gonadotropins alone.
13.4 Cycle Monitoring to Individualize Dose Adjustments in Ovarian Stimulation
The response to stimulation is monitored with serial measurements of serum estradiol and transvaginal ultrasound imaging of ovarian follicles. The first serum estradiol level usually is obtained after 3–5 days of stimulation to determine whether the chosen dose of gonadotropins requires adjustment. Thereafter, serum estradiol concentrations and ovarian scans are obtained every 1–3 days, based on the quality of the response and the need to evaluate the impact of any further adjustments in the dose of gonadotropin treatment. Most women require a total of 9–10 days of stimulation. In general, the goal is to have at least two follicles measuring 17–18 mm in mean diameter, ideally accompanied by a few others in the 14–16 mm range, and a serum estradiol concentration that is consistent with the overall size and maturity of the cohort (approximately 200 pg/ml per follicle measuring 14 mm or greater). Typically, endometrial development is also monitored during stimulation by measuring the endometrial thickness. Although multiple studies have examined the prognostic value of endometrial thickness and echotexture in ART cycles, the issue remains controversial. The results are best when endometrial thickness measures 8–9 mm or greater and poor when the endometrium is less than 6–7 mm in thickness or appears homogeneous on the day of hCG administration. Once the targeted thresholds of response are met, hCG (10,000 IU) is administered to induce final follicular maturation.
13.5 Individualization on the Basis of Patient Response
13.5.1 High Responders
Occasionally, stimulation generates an exaggerated follicular response, characterized by massive ovarian enlargement, extremely large numbers of follicles of all sizes, and markedly elevated serum estradiol concentrations (>3,000 pg/ml). Under such circumstances, the risk for ovarian hyperstimulation syndrome is substantially increased and may lead to cycle cancelation.
Canceling the cycle and starting another using a more conservative stimulation regimen may ultimately decrease overall costs and maximize the chances for success. The prognosis for high responders in subsequent cycles is generally very good. Hence, in a woman with PCOS, the stimulation is always at a lower dose.
13.5.2 Poor Responders
The challenges presented by “poor responders” are far greater. Poor responders include women in whom a previous cycle yielded three or fewer oocytes or was canceled because of observations of three or fewer follicles 16 mm or greater, a single dominant follicle, or a peak serum estradiol less than 500 pg/ml. In such women, a more aggressive or alternative stimulation regimen is warranted, and there are several options from which to choose:
· The long protocol, beginning with higher doses of gonadotropin stimulation.
· Decreasing the doses of GnRH agonist or discontinuing agonist treatment immediately before or soon after gonadotropin stimulation begins. However, in agonist cycle, the response in a poor responder is not good.
· A short follicular phase GnRH agonist treatment regimen using a standard or microdose “flare” protocol.
· Using a GnRH antagonist instead of a long-acting agonist.
13.6 Individualizing Controlled Ovarian Stimulation for Prevention of Ovarian Hyperstimulation
Ovarian hyperstimulation syndrome (OHSS) is an exaggerated response to ovulation induction therapy. The OHSS is typically associated with exogenous gonadotropin stimulation and is only rarely observed with the use of other agents. Clinicians who prescribe ovulation-inducing agents must be prepared to recognize and manage OHSS .
The syndrome has a broad spectrum of clinical manifestations, from mild illness needing only careful observation to severe disease requiring hospitalization and intensive care [12, 13].
13.6.1 Risk Factors
The following factors increase the risk independently for developing OHSS :
· Young age
· Low body weight
· Polycystic ovary syndrome (PCOS)
· Higher doses of exogenous gonadotropins
· High absolute or rapidly rising serum E2 levels
· Previous episodes of OHSS
Ovulation induction regimens need to be individualized, carefully monitored, and used with the minimum dose and duration of gonadotropin therapy necessary to achieve the therapeutic goal. Caution is indicated when any of the following indicators for increasing risk of OHSS are present:
· Rapidly rising serum E2 levels
· An E2 concentration in excess of 2,500 pg/ml
· The emergence of a large number of intermediate-sized follicles (10–14 mm)
Withholding further gonadotropin stimulation and delaying hCG administration until E2 levels plateau or decrease significantly can reduce risks of OHSS . A lower dose of hCG may be prudent for patients judged to be at a high risk for OHSS. The use of exogenous P (e.g., 50 mg P in oil IM, 200 mg P vaginal suppositories, or 8 % P vaginal gel, daily) for luteal phase support rather than supplemental doses of hCG may further reduce the risks of OHSS.
Another method is “coasting” or “controlled drift” – here further gonadotropin stimulation is stopped and administration of the ovulatory trigger is deffered till the estradiol concentration has returned to “safe” levels. The general consensus is that coasting should be initiated when the serum estradiol levels exceed 3,000 pg/ml but not unless the leading follicle is 15–18 mm in diameter; the duration should not exceed 4 days as reduced implantation and pregnancy rates are seen when the coasting is done for longer periods of time. A GnRH analog can be used in antagonist cycle instead of hCG.
Serum progesterone must be controlled during the ovarian stimulation cycle in order to avoid premature luteinization. Regarding the effect of GnRH antagonists on human endometrium, Simon et al. studied the gene expression profile on the endometrium of women undergoing ovarian stimulation for oocyte donation and observed that the endometrial development after GnRH antagonist mimics the natural endometrium more closely than after GnRH agonist .
One of the significant advantages that antagonists have over agonists is the duration of the analog used. The initial flare effect of the agonist necessitates the longer duration of treatment to achieve adequate downregulation. GnRH antagonists competitively block pituitary receptor sites and induce a rapid and reversible suppression of gonadotropins. The reduction in both duration of therapy and gonadotropin requirement make its use attractive.
Each woman is different in her capacity to produce mature oocytes with the controlled ovarian stimulation. In clinical practice the dosage is decided by the age of the woman, antimullerian hormone levels, basal antral follicle counts, and presence or absence of polycystic ovary syndrome. Many factors are interdependent, and hence, a careful selection of the type of ovarian stimulation will be the key factor in deciding the success of the same.
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