© Springer India 2015
Surveen Ghumman (ed.)Principles and Practice of Controlled Ovarian Stimulation in ART10.1007/978-81-322-1686-5_1313. Individualizing Ovarian Stimulation Protocols in ART
(1)
Department of Obstetrics and Gynaecology, Manipal Assisted Reproduction Centre, Kasturba Medical College, Manipal University, Manipal, Karnataka, 576104, India
Abstract
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.
Keywords
IndividualizingStimulationOvarian reserveAMHMonitoringAntagonistAgonistGonadotropinHyperstimulation13.1 Introduction
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 [1]. AMH of >3.5 ng/ml predicted hyper-response and OHSS. AMH levels are higher in PCOS [2]. 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 [3]. 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 [4]. 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 [5].
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 [6]. 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 [7].
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 [8]. 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.
13.3.1.1 Disadvantage
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.
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