Part five of the expert cycle: “Standard methods of ovarian stimulation” presents the methods of ovarian stimulation. Anovulation may be caused by a number of diseases the adequate treatment of which is more appropriate than pharmacological induction of ovulation. All women with anovulation should be subjected to initial diagnosis, at least for thyroid dysfunction and hyperprolactinemia.
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Standard methods of ovarian stimulation
Ovulation induction is a procedure broadly applied in infertility treatment. It consists in controlled stimulation of ovulation in order to increase the chances for fertilization or for obtaining the egg cells for the performance of IVF procedure./p>
Female infertility may be caused by ovulation disorders in as much as 40%. The modern methods of ovarian stimulation are very effective, so if anovulation is the only cause of problems with fertilization, the application of the therapy of this type has very good prospects. In addition, if the cause of this disorder responds to treatment, the frequency of pregnancies obtained with ovulation induction can be comparable to that observed in healthy population.
Prior to initiation of this type of therapy, the patient should undergo the appropriate diagnostic procedures in order to confirm anovulation or ovulation disorders. The relevant information can be obtained from the medical interview. Attention should be paid to the regularity of menstrual cycle, character of cervical mucus, additional symptoms like abdominal pain approx. 16–14 before menstruation. According to the position expressed by ESHRE, among all hormonal tests, only the determination of progesterone in the middle luteal phase provides information whether the cycle is ovulatory. Other tests, like methods of detecting LH peak, cervical mucus examination, basic temperature measurements, have low sensitivity and specificity. If the patient menstruates regularly every 28 days, blood progesterone level on cycle day 21 is determined; if the length of the patient’s cycle is different (25-35 days), progesterone level should be checked approximately one week before the expected beginning of the menstruation, i.e. at the time when the hormone concentration reaches or oscillates close to its peak. Concentration exceeding 30 nmol/l confirms the occurrence of ovulation in such cycle. However, progesterone level below 3 ng/ml usually indicates anovulation. The exception would be the situation where the hormone level was determined immediately after ovulation or just before the menstruation, when the levels of this hormone are physiologically low.
Anovulation may be caused by a number of diseases where their adequate treatment is more appropriate than pharmacological induction of ovulation. The abnormal function of ovaries may result from thyroid diseases, obesity, excessive weight loss, intensive sport activities, polycystic ovary syndrome, hypothalamic pituitary failure, hyperprolactinemia. All women with anovulation should be subjected to initial diagnosis, at least for thyroid dysfunction and hyperprolactinemia.
WHO divides the causes of ovulation disorders into the following groups:
Group I: Hypothalamic pituitary failure. This group includes patients with hypothalamic amenorrhea caused by stress, weight loss, intensive physical exercises, anorexia nervosa and variants of this disease, Kallmann syndrome and isolated gonadotropin deficiency. Patients with hypothalamic or pituitary tumor are excluded from this group. Typically, these women are diagnosed with hypogonadotropic hypogonadism with low levels of follitropin (FSH) and estrogens and normal levels of prolactin.
Group II: Hypothalamic-pituitary-ovarian dysfunction. This group includes women with amenorrhea or oligomenorrhea with or without the features of hyperandrogenism, and women with polycystic ovary syndrome. In these patients, levels of FSH, estrogens and prolactin are normal.
Group III: Ovarian failure. This group includes patients with amenorrhea and with high serum FSH level indicative of ovarian failure.
Groups of medications used for ovarian stimulation:
1. Clomiphene citrate – estrogen antagonist
The particles of this medication form long-term binding to estrogen receptors. Receptors blocked in this way are not stimulated by estrogens circulating in the blood. Hypothalamus reads this as the signal of low level of these hormones and, by way of negative feedback, starts to be stimulated to secrete more gonadoliberins. Clinical studies in anovulatory women showed 80% efficacy of this medication in the scope of ovulation induction and 50% efficacy in the scope of obtaining pregnancy in patients with induced ovulation.
Clomiphene is the drug of choice in anovulatory infertile women with normal thyroid function, normal serum prolactin levels and without galactorrhea, with the evidence of endogenous estrogen secretion in the form of clinical signs. However, it does not show efficacy in women with hypogonadotropic hypogonadism (group I according to WHO). There are no grounds for suspecting that the decrease in the level of estrogens induced by clomiphene activates the mechanism of negative feedback as low estrogen levels present in these patients do not cause such effect. In these women, usually another treatment method is applied, consisting in direct stimulation of pituitary gland (exogenous pulsatile GnRH) or of ovaries (exogenous gonadotropins). Use of clomiphene citrate in patients with luteal phase failure is justified. Short luteal phase, the most serious disorder in this group, is associated with abnormally low levels of FSH in follicular phase. Clomiphene citrate causes the increase in FSH level. This is why it is the drug of choice in these patients. In addition, after clomiphene treatment, progesterone levels are higher than in spontaneous cycles, probably in the result of optimized follicular growth and due to the formation of more than one corpus luteum. Young women with short period of unexplained infertility and women who do not accept or have contraindications to more aggressive therapy also can be subjected to stimulation with clomiphene citrate. Its efficacy in women with unexplained infertility may result from the correction of undiagnosed luteal phase failure or causing “superovulation” due to the release of more than one egg cell. The empiric clomiphene therapy is the most effective in combination with intrauterine insemination (IUI) which allows to increase the number of both egg cells and sperm.
Clomiphene citrate is used most often from cycle day 2 or 3 for 5 days at the dose of 50-150 mg/day. The clomiphene dose needed for ovulation induction correlates with body mass.
Clomiphene is typically administered for 4-5 cycles. If the patient does not get pregnant in this time period, treatment with gonadotropins should be considered.
If the cycle is stimulated before the planned intrauterine insemination (IUI), then, after the growing follicles have shown the features of maturity, a pharmacological ovulation peak should be caused – with a one-time intramuscular injection of 5000–10000 IU hCG approx. 36 hours before the procedure.
Induction with clomiphene citrate requires monitoring. A serially performed transvaginal ultrasound allows to show the size and number of growing follicles and provides the evidence of presumed ovulation. A control ultrasound and cervical mucus evaluation should be carried out on cycle day 10–12.
In the properly selected group, clomiphene effectively induces ovulation in approximately 80% patients. The probability of successful therapy decreases with age, body mass index (BMI) and the severity of concomitant hyperandrogenism. Among anovulatory women in whom ovulation occurs in response to clomiphene treatment, the pregnancy rate amounts to approximately 15% per cycle. In women without other infertility factors, this rate reaches 22%, which is comparable to the rate observed in fertile couples.
Side effects of clomiphene citrate include hot flashes, night sweats, breast discomfort, headache, mood changes, feeling of pressure or pain in pelvis, nausea, vomiting. Vision disorders (blurred vision, diplopia, floaters, waves, unspecified visual complaints, hypersensitivity to light) are rare (in less than 2% of patients).
Potential complications when using this preparation may include multiple pregnancies (the risk increases to approximately 5-8%) and ovarian hyperstimulation syndrome. Ovarian hyperstimulation is observed less frequently than for gonadotropin treatment, and if it occurs, it is mild. There is no significant evidence that the clomiphene treatment increases the general risk of congenital defects or the risk of any specific defect. The number of miscarriages does not differ from that observed in spontaneous pregnancies. A meta-analysis of the results of eight clinical control trials demonstrated that the treatment of nulliparous women with drugs used in infertility treatment is associated with a slight increase in the incidence of serous tumors of borderline malignancy, but not of invasive carcinomas. There has been no evidence of increased total risk of breast cancer in women who took clomiphene citrate.
2. Exogenous gonadotropins
Ovulation induction with exogenous gonadotropins should be considered in patients with hypogonadotropic hypogonadism (hypothalamic amenorrhea, group I according to WHO classification). In this case, clomiphene and related drugs are ineffective, because a preserved and properly functioning hypothalamic-pituitary-ovarian axis is necessary for their action. Women with hyperprolactinemia-related secondary hypogonadotropic hypogonadism and with intolerance to dopamine antagonists also become candidates for gonadotropin therapy. Similarly, induction with gonadotropins is indicated also in patients who failed attempts at induction of ovulation with clomiphene citrate. Gonadotropins can also be used to stimulate the growth and release of more than one mature egg cell with the aim to increase the chances of pregnancy in older women with limited fertility and in patients with infertility unexplained by other causes. Superovulation is the most effective in combination with well-timed intrauterine insemination
These medications are extremely potent and highly effective. However, gonadotropin treatment is very costly. The use of gonadotropins carries the significant risk of multiple pregnancy and of ovarian hyperstimulation syndrome. For this reason, in order to induce ovulation but at the same time minimize this risk, the treatment with gonadotropins has to be precisely monitored by means of serial determinations of serum estradiol concentration and ultrasound assessment of ovaries.
Two main techniques of gonadotropin administration are recommended.
Increasing-dose treatment regimen
It is indicated in women with hypogonadotropic hypogonadism (group I according to WHO), and in clomiphene-resistant anovulatory women (group II according to WHO). According to this regimen, induction of ovulation should be started with low daily doses (75 UI). This method allows determining the effective response threshold. When using this method, blood estradiol level is monitored and the size and number of growing ovarian follicles is assessed by means of ultrasound examination. Then the gonadotropin dose may be maintained or increased, as appropriate.
Women with polycystic ovary syndrome are often particularly sensitive to stimulation with low gonadotropin doses. Therefore, it is prudent to carry out early and frequent monitoring of the therapy. In turn, insulin-resistant women may be less sensitive to stimulation than women without insulin resistance. Treatment with metformin prior to and in the course of stimulation with gonadotropins helps to improve the response, decrease the number of growing ovarian follicles and decrease the likelihood of therapeutic cycle termination in the result of hyperstimulation.
Decreasing dose treatment regimen
The treatment starts with higher doses (150-225 IU per day) which are decreased gradually in order to promote the growth of only the most sensitive dominant follicle and avoid the stimulation of less sensitive, smaller follicles in the cohort. This treatment method should be preferably used only after the determination of the response threshold in one or more earlier stimulated cycles.
These two treatment regimens can be effectively combined, initially by gradually increasing the gonadotropin doses until the response is observed, and then by decreasing the doses until the dominant follicle appears.
In women with hypogonadotropic hypogonadism, the rate of pregnancy per cycle is approximately 25%, i.e. it is equal to or higher than in women with normal fertility. The total pregnancy ratio after six cycles of stimulation with gonadotropins amounts to 90%.
The total incidence of spontaneous abortions in pregnancies after gonadotropin-induced cycles is approximately 20-25%, which means that it is moderately higher than usually observed in clinical settings (15%).
Just like in case of clomiphene, there is no evidence of more frequent occurrence of congenital anomalies in relation to gonadotropin treatment.
Ovarian hyperstimulation syndrome
Mild ovarian hyperstimulation (transient discomfort in abdominal cavity, mild nausea, vomiting, diarrhea and increased abdominal circumference) is not rare but requires only expectant management. If the induction of ovulation is carried out as recommended, with increasing doses – which allows to determine the lowest effective dose – the risk of hyperstimulation syndrome (massive enlargement of ovaries, increasing body mass, intensive abdominal pain, unrestrained nausea and vomiting, large ascites, oliguria) is low. However, if it occurs – serious consideration should be given to hospitalization which will allow for more accurate monitoring and more aggressive treatment.
The risk factors of ovarian hyperstimulation syndrome include: young age, low body mass, polycystic ovary syndrome, higher doses of gonadotropins and previous episodes of hyperstimulation. The risk increases with the increase in the estradiol level and in the number of growing ovarian follicles, as well as after the additional introduction of hCG doses after ovulation with the aim to support the luteal phase.
No causal relationship between the treatment with exogenous gonadotropins and the breast or ovarian cancer has been established; nevertheless, if the chance of success is small, long-term treatment with gonadotropins should be avoided.
Hypothalamic system failure with maintained pituitary sensitivity to gonadoliberins (GnRH) is the main indication to ovarian stimulation with GnRH. A permanently connected pump releases GnRH in pulsatile fashion, thus imitating the secretion cycle occurring in healthy women. In consequence, the obtained levels of pituitary gonadotropins correspond to the physiological levels. This allows the proper regulation of the feedback mechanism by the action of ovarian steroids and peptides. In consequence, follicle recruitment, selection, growth and maturing occur just like in a normal menstrual cycle .
Due to the low risk of hyperstimulation syndrome, monitoring of stimulation is not necessary. The control of the potential effect should be carried out by means of ultrasound examination and serum estradiol level determination.
The best candidates to ovulation induction with exogenous GnRH are infertile women with anovulation and hypogonadotropic hypogonadism because in their case such treatment is specific, physiological and very effective. GnRH administration by means of an infusion pump is also effective in case of women with hyperprolactinemia and is an alternative for exogenous gonadotropins in case of failure of or intolerance to the treatment with dopamine agonists.
In women with polycystic ovary syndrome, hormonal response to pulsatile administration of GnRH is clearly abnormal. It is possible to obtained normalization by means of daily subcutaneous injections of long-acting GnRH agonists. The treatment should be applied within 6-8 weeks preceding the planned gonadoliberin treatment.
The great advantage of this method is that it rarely causes the growth and ovulation of many follicles. Therefore, the risk of multiple pregnancy is much lower and the risk of ovarian hyperstimulation is nearly entirely eliminated.
4. Ovulation induction with dopamine agonists
Hyperprolactinemia is the fourth specific condition associated with anovulation. Prolactin inhibits the pulsatile secretion of GnRH. Dopamine agonists inhibit pituitary prolactin secretion and in consequence restore the proper function of hypothalamic-pituitary-ovarian axis. These medications are effective irrespective of the prolactin source, as even the pituitary adenomas which secrete it are sensitive to their action.
Treatment with dopamine agonists normalizes and maintains the normal prolactin concentration in approximately 60-85% women with hyperprolactinemia. Normal menstrual cycles return in 70-90% of patients usually after 6-8 weeks from the initiation of treatment, while ovulatory cycles return in 50-75% of the treated women irrespective of the presence of a pituitary adenoma. However, even as many as 12% women subjected to this therapy discontinue it due to the experienced side effects.
Insulin resistance and hyperinsulinemia are currently considered the basic disorders in women with polycystic ovary syndrome. They contribute to a significant extent to hyperandrogenism and chronic anovulation which are characteristic for this syndrome. Infertile anovulatory women with polycystic ovary syndrome and hyperinsulinemia are typically more resistant to clomiphene treatment. Decreasing insulin resistance through body mass decrease or use of metformin significantly reduces the patients’ resistance to clomiphene.
In obese, infertile, anovulatory women with polycystic ovary syndrome, decrease in body mass in itself (by 5% or more) reduces hyperinsulinemia and hyperandrogenism often restoring ovulatory cycles. The combination therapy with metformin and clomiphene allows to obtain ovulation 4-9 times more often than in the case of clomiphene in monotherapy, and often leads to the induction of ovulation in cases where monotherapy with clomiphene failed. In general, in 70-90% of women with anovulation in polycystic ovary syndrome, treated with metformin, ovulation occurs spontaneously or after the additional introduction of clomiphene.
6. Laparoscopic ovarian drilling
It is the rational therapeutic option for infertile, anovulatory, clomiphene-resistant women, but due to transient effects of treatment, risk of postoperative adhesions and theoretical risk of adverse impact on ovarian reserve, detailed analysis needs to be conducted. This procedure should be preferably reserved for women who can’t or don’t want to accept the costs and risks associated with gonadotropin treatment. In all cases, the procedure should be carried out in a manner that best saves the egg cells.
Authors of the article: Magdalena Kaszuba-Modrzejewska, MD; professor Krzysztof Łukaszuk, PhD, MD, Chief of INVICTA Fertility Clinics
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