Ovulation Induction

Jon C. Havelock and Karen D. Bradshaw Introduction

Approximately 25% of infertility can be attributed to ovulatory disorders. The goal of ovulation induction is to restore fecundity by restoring regular, ovulatory cycles. Ovulation induction may also be used for controlled ovarian hyperstimulation (COH) for treatment of other causes of infertility such as mild/moderate en-dometriosis, unexplained infertility, and for assisted reproductive techniques such as in vitro fertilization (IVF). When used in ovulatory patients, the goal of ovulation induction is not to restore ovulatory cycles but to increase fecundity through ovarian stimulation (Table 15.1).

The World Health Organization (WHO) has provided a simplified classification system for disorders of ovulation. This grouping system describes the etiology of anovulation, and the most appropriate treatment for patients with ovulatory dysfunction is determined by their classification. WHO Group I patients have low follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels and low estradiol levels. These patients have hypothalamic-pituitary hypofunction, either congenital or acquired and have a negative progestin challenge test due to low endogenous estradiol levels. WHO group II patients have normal FSH and LH levels, and normal estradiol levels. Most anovulatory patients fall within this category, and >90% of these patients have polycystic ovarian syndrome (PCOS). These patients will have a positive progestin challenge test due to normal endogenous estradiol levels. WHO group III patients have elevated FSH and LH levels. Gonadotropins are elevated (often in the menopausal range) secondary to ovarian follicle depletion. These patients respond poorly to ovulation induction and are candidates for IVF-oocyte donation. Finally, hyperprolactinemic patients (WHO group V/VI), with or without a pituitary adenoma, may have ovulatory dysfunction. Elevated prolactin levels interfere with gonadotropin releasing hormone (GnRH) pulsatility and, as a result, impair ovulation.

Testing Prior to Ovulation Induction

Since ovulation induction is pursued in the course of fertility treatment, a comprehensive fertility investigation should be performed prior to instituting therapy. A thorough history and complete physical examination of the female and male partner should be undertaken. Basic investigations for anovulation should include a day 3 FSH level (or random FSH if amenorrhea), thyroid stimulating hormone (TSH) level, and prolactin level. A progestin challenge test may be performed to determine the estrogen status and serves to help distinguish WHO group I from group II. A semen analysis should be performed as 25-40% of infertility has a male-factor component. A hysterosalpingogram may be ordered initially to evaluate uterine and

Table 15.1. Ovulation induction treatment and indications

Etiology

Primary treatment

Secondary treatment

Adjuvant treatment

WHO Group I

Hypogonadotropic hypogonadism

Gonadotropins

Pulsatile gonadotropin releasing hormone

Intrauterine insemination

WHO Group II

Eugonadotropic hypogonadism

Weight Loss Clomiphene citrate Metformin

Aromatase inhibitors Gonadotropins

Laparoscopic ovarian diathermy Glucocorticoids Intrauterine insemination

WHO Group III

Hypergonadotropic hypogonadism

Oocyte donation

Intrauterine insemination

WHO Group V/VI

Hyperprolactinemia

Dopamine agonists Gonadotropins

Intrauterine insemination

Ovulatory Infertility

Unexplained infertility Endometriosis Male-Factor infertility IVF

Clomiphene citrate or gonadotropins Clomiphene citrate or nipl gonadotropins

Intrauterine insemination tubal anatomy, but this may be delayed in an anovulatory patient if there is no evidence of uterine/tubal disease on history and or physical examination. In hyperandrogenic PCOS patients, serum testosterone, dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxyprogesterone levels may be obtained to determine the origin of the elevated androgens. A pelvic ultrasound may be performed as part of the 2003 criteria for PCOS diagnosis. These basic investigations ensure that the cause of anovulation is obtained and determine whether other causes of infertility are present. If other infertility factors are present, these may require additional treatments that are not addressed with ovulation induction, alone.

Ovulation Induction Monitoring

The goal of ovulation induction is to maximize the chance of pregnancy while minimizing the complications, namely multiple pregnancy and ovarian hyperstimulation syndrome (OHSS). This is facilitated through ovulation induction monitoring. Ovulation induction monitoring may take the form of a menstrual diary, urine or serum LH measurements, or serial ultrasound with or without serial estradiol measurements. Since ovulation induction is used in conjunction with timed intercourse or intrauterine insemination (IUI), efforts are made to time ovulation with the presence of fresh sperm in the female reproductive tract. Since the oocyte has a lifespan of approximately 24 hours in the female genital tract, and sperm can survive up to 72 hours, the best chance for conception occurs if the sperm are present at the time of, or just prior to ovulation. Ovulation occurs 34-36 hours after the start of the LH surge, 17-26 hours after urine LH detection, and at a follicular diameter of 20-27 mm. Furthermore, when ultrasound is used to monitor follicle development and human chorionic gonadotropin (hCG) is administered for final oocyte maturation (a pharmacological mimic of the LH surge), it appears that 15 mm is the smallest follicular size sufficient for ovulation. These surrogate markers for ovulation serve as a guideline for timing of intercourse or IUI.

Estradiol levels are often used in conjunction with ultrasound for monitoring ovulation induction cycles. In unstimulated, monofollicular cycles, estradiol and follicle size show a highly correlated linear increase in the five days preceding ovulation, with a daily increase in follicular diameter of 1.2-2 mm/day (Randall and Templeton, 1991) and a corresponding increase in estradiol to an average preovulatory estradiol of 250 pg/ml. In COH cycles, greater preovulatory follicle numbers and estradiol levels are seen. Compared to natural cycles, there is a weaker correlation between follicle numbers and estradiol levels in multifollicular development. Nonetheless, estradiol levels typically reach 250 pg/ml per preovulatory follicle.

Ultrasound monitoring of ovulation induction serves an additional purpose in monitoring endometrial development. A periovulatory endometrial thickness of > 10 mm is a good prognostic factor for conception in COH cycles, and endometrial thickness of <7 mm is associated with a very poor likelihood of pregnancy. The finding of a thin endometrium by ultrasound gives prognostic information that may allow for changes in treatment to promote endometrial development.

Complications of Ovulation Induction

Multiple Pregnancy

One of the greatest concerns in ovulation induction is multiple pregnancy, especially higher order multiple pregnancy (triplets or greater). Multiple pregnancy is associated with significantly higher perinatal morbidity and mortality,

primarily related to premature birth. Risk factors for higher order multiple pregnancy in ovulation induction include: age <32 years, PCOS diagnosis, estradiol >2000 pg/ml, ovulation induction with gonadotropins, and when more than three follicles are >14 mm. With careful monitoring of cycles, the risk of multiple pregnancy can be decreased.

Ovarian Hyperstimulation Syndrome (OHSS)

Ovarian hyperstimulation syndrome is a clinical syndrome encompassing a constellation of signs and symptoms, including abdominal pain and distension, ovarian enlargement, nausea and vomiting, and ascites. Severe cases may include hydrothorax, oliguria, increased hematocrit, decreased renal function, and thromboembolic complications. Numerous severity classification systems have been described, and hospitalization is required in severe instances. The risk factors for OHSS are similar to the risk factors for multiple pregnancy: estradiol level >3000 pg/ml, large numbers of follicles and in younger age. For OHSS the best cure is prevention. Ovarian hyperstimulation syndrome does not occur in the absence of ovulation. In ovulation induction cycles deemed to be at risk for OHSS, cycle cancellation and withholding the injection for final follicular maturation (discussed later) will usually prevent OHSS. Another commonly used method of prevention of OHSS involves "coasting." This involves terminating the ovulation induction medication (gonadotropins) once the largest follicle is >14 mm, for 1-4 days, and the estradiol level is <3000 pg/ml. Other methods of prevention and treatment of OHSS are beyond the scope of this chapter.

Methods of Ovulation Induction

The majority of patients seeking ovulation induction are women with PCOS. An ovulation induction treatment algorithm for women with PCOS can be seen in Figure 15.1.

Weight Loss

Weight loss can restore ovulatory cycles for many women with PCOS. Approximately 80% of women with PCOS are obese, which is associated with hyperinsulinemia. The increased insulin has a direct effect on the ovary, resulting in increased androgen production. Weight loss of >5% has been shown to restore ovulation in some PCOS women. In addition, PCOS women who did not conceive with previous treatment and had a mean weight loss of 10.2 kg went on to have a 77% pregnancy rate with treatment. While this is an often overlooked mode of treatment, it should be considered first line treatment for overweight women with PCOS.

Clomiphene Citrate

Clomiphene citrate (CC) is an estrogen analog that was first shown to induce ovulation in 1961 and was approved for clinical use in the United States in 1967. Clomiphene belongs to a family of compounds known as selective estrogen receptor modulators (SERMs). Other well-known SERMs include tamoxifen (breast cancer treatment) and raloxifene (osteoporosis treatment). Clomiphene is used for ovulation induction or controlled ovarian hyperstimulation in patients with normal endogenous estrogen levels.

Clomiphene exerts both estrogen agonist and antagonist effects. Clomiphene blocks the negative feedback of endogenous estrogen at the hypothalamic and

Polycystic Ovarian Syndrome Etiology

Figure 15.1. Ovulation induction treatment algorithm for polycystic ovarian syndrome (PCOS). DHEAS, dehydroepiandrosterone sulfate; IVF, in vitro fertilization.

Figure 15.1. Ovulation induction treatment algorithm for polycystic ovarian syndrome (PCOS). DHEAS, dehydroepiandrosterone sulfate; IVF, in vitro fertilization.

pituitary levels. This results in a >50% increase in endogenous FSH which subsequently stimulates follicular growth. Ovulation rates approach 80%, with cumulative pregnancy rates of 30-40% over the course of a few cycles. This discrepancy between ovulation and pregnancy rates is thought to be due to the estrogen antagonist effects on the endometrium and cervical mucus. This may be detected by an endometrial thickness of <7 mm on ultrasound, which would suggest other forms of ovulation induction would be more effective.

Clomiphene citrate (CC) is administered in a dose of 50-150 mg/day for 5 days, starting on day 2, 3, 4, or 5 of the menstrual cycle. The lowest starting dose is used initially and is only increased in subsequent cycles if the patient remains anovula-tory at a given dose. While some physicians have used longer treatment regimens and higher doses, there is little evidence for effectiveness at doses greater than 150 mg. Once a patient is ovulatory with CC treatment, it is usually continued for up to 3-6 ovulatory cycles. Approximately 75% of conceptions occur in the first three treatment cycles. Ovulation can be confirmed with a single mid-luteal (7 days after ovulation) serum progesterone level of >5 ng/ml.

Monitoring of clomiphene citrate cycles may be managed using ovulation prediction kits, basal body temperature monitoring, or ultrasound monitoring. If the woman is attempting conception in conjunction with timed intercourse, the fertile period is a 6-day period which is generally the day of ovulation and the 5 days preceding ovulation (Dunson et al, 1999), and intercourse every second day is recommended. If ovulation induction is used in conjunction with IUI, then the IUI should be performed the day of, or the day following a positive ovulation predictor test. Ultrasound monitoring of CC stimulated cycles has demonstrated that on the day of spontaneous LH surge, the preovulatory follicles are usually slightly larger than in natural, unstimulated cycles. If ultrasound monitoring is used in conjunction with IUI, hCG (5,000-10,000 IU) is typically administered when the lead follicle is >18 mm, and IUI is performed 36 hours later. While high-technology monitoring has not been shown to increase pregnancy rates over low-technology monitoring, ultrasound monitoring adds additional information on the endome-trial effects of CC.

Complications of CC include OHSS and multiple pregnancies. Original reports demonstrated twin pregnancy rates of 10% and higher order multiple rate (triplets or greater) of 1%. Clinically significant OHSS is uncommon in CC stimulated cycles. Side effects of CC include breast tenderness, bloating, hot flashes, abdominal discomfort, and mood changes. A rare side effect is changes in vision or sensitivity to light, which requires immediate discontinuation of the medication, as continuation may cause permanent visual changes.

Metformin

There has been a plethora of evidence that PCOS is associated with hyperinsulinemia, which leads to the widespread use of insulin sensitizing agents for treatment. The most studied agent is the oral biguanide, metformin. The exact mechanism of action of metformin in PCOS is unclear, but may be related to weight loss or direct suppression of androgen production by the ovary. Metformin is typically used at doses between 1500-2000 mg/day, and the main side effect is GI upset.

Metformin may be used alone or in conjunction with CC. When metformin is used alone as an ovulation induction agent, ovulation rates are typically between 30-40%, but evidence for a significant increase in pregnancy rates is lacking. When metformin and CC are used together, ovulation rates approach 90%. In patients who did not previously ovulate with CC therapy, ovulation rates are approximately 75% when treated with CC plus metformin. A recent meta-analysis suggests that CC plus metformin has an approximately 3-fold greater pregnancy rate in PCOS women than CC alone. In clinical practice, metformin is usually used in conjunction with CC in obese PCOS patients or in patients who do not respond to CC. Currently, a large, randomized, double-blind, clinical trial comparing pregnancy rates in patients treated with CC, metformin, or CC plus metformin, is ongoing. This trial should determine the best treatment regimen for achieving pregnancy.

Aromatase Inhibitors

Aromatase inhibitors are orally active agents that inhibit estrogen biosynthesis by inhibiting the aromatase enzyme, resulting in decreased circulating levels of es-tradiol. Under low estrogen conditions, there is decreased negative feedback and greater pituitary FSH release. While this medication is not approved for ovulation induction, it is increasingly being used for this purpose. The most commonly used aromatase inhibitor given for ovulation induction is letrozole. It is typically administered at a dose of 2.5-7.5 mg/day for a 5-day regimen, starting on day 3 of the menstrual cycle or occasionally as a single 20 mg dose given on day 3. While aromatase inhibitors have not been shown to be superior to CC, there are some studies that suggest they may be useful in patients who do not respond to CC.

Laparoscopic Ovarian Diathermy

Laparoscopic ovarian diathermy (LOD) is an endoscopic surgical procedure that has been found to be an effective mode of ovulation induction. This procedure involves creating 3-10 holes per ovary with an electric current or laser (see Chapter 14). Its use has primarily been in the CC resistant population, and a randomized, controlled study in this population has shown similar pregnancy rates in patients undergoing LOD compared to gonadotropin therapy. Furthermore, LOD has been shown to have equivalent pregnancy rates after 6-12 months when compared to 3-6 cycles of gonadotropin therapy with significantly lower multiple pregnancy rates in the LOD group. A recent study comparing metformin treatment versus LOD in a CC resistant population demonstrated similar ovulation rates, but higher pregnancy rates in the metformin group. With an expanding number of ovulation induction agents, the role of LOD in contemporary ovulation induction appears to be limited.

Glucocorticoids

While not an ovulation induction agent on its own, glucocorticoids (namely dexamethasone) have occasionally been used in conjunction with CC in women who are unresponsive to CC. A subset of patients with PCOS have increased adrenal androgen production, reflected by elevated DHEAS levels. Administration of dexamethasone suppresses adrenal androgen production and can increase the ovulation rate among women with DHEAS levels >200 |ig/dl. The most widely used protocol includes dexamethasone administered at nighttime in a dose of 0.5 mg orally in conjunction with CC treatment.

Pulsatile Gonadotropin Releasing Hormone

Gonadotropin releasing hormone (GnRH) was first identified in 1971 and is the hypothalamic releasing hormone responsible for FSH and LH synthesis and release from the pituitary. While it is rarely used in clinical practice, it is the most physiological method of ovulation induction for WHO group I ovulatory disorders, namely women who have hypogonadotropic hypogonadism. These women typically do not have the pulsatile GnRH secretion required for the synthesis and release of gonadotropins from the pituitary that are responsible for ovarian folliculogenesis and regular, cyclic menses. GnRH is typically administered in doses from 2.5-20 |ig every 60-120 minutes. GnRH pulsatile therapy may be administered intravenously (IV) or subcutaneously (SC) but appears to be more effective by IV route. The LH surge and subsequent ovulation occur spontaneously, therefore not requiring an injection of hCG to induce follicular maturation, and pulsatile GnRH can be continued in the luteal phase to provide support for the corpus luteum. Ovulation rates are typically 75%/cycle, with pregnancy rates of 23%/ovulatory cycle and multiple pregnancy rate of 3.8%/cycle. The low multiple pregnancy rate is due to monofollicular development using this method of ovulation induction. In spite of high pregnancy rates and low multiple pregnancy rates, due to the need for a pump and indwelling catheter, this method of ovulation induction is not frequently used.

Dopamine Agonists

Dopamine agonists are the first-line therapy for patients with anovulation related to hyperprolactinemia. Hyperprolactinemia is often due to prolactin-secreting pituitary adenomas. Hyperprolactinemia interferes with GnRH pulsatile secretion, thereby causing anovulation. Dopamine inhibits prolactin secretion, and administration of

dopamine agonists results in both a decrease in tumor volume and restoration of ovulatory cycles. The most commonly used dopamine agonist for ovulation induction is bromocriptine, which is administered in a dose of 2.5-10 mg, daily in divided doses. Cabergoline is another dopamine agonist with a better side-effect profile and patient tolerability and is administered in a dose of 0.25-1 mg, given twice weekly. Cumulative pregnancy rates of 80% can be expected with bromocriptine treatment for anovulation due to hyperprolactinemia. Dopamine agonists are typically stopped once conception has occurred.

Gonadotropins for Ovulation Induction

Background

The anterior pituitary gonadotropins, LH and FSH, and the placental gonadotropin, hCG, are the three identified gonadotropins and all are used in ovulation induction. LH serves two distinct and essential functions. First, it is responsible for stimulating the synthesis of ovarian androgens in ovarian theca cells. These androgens serve as precursors for ovarian estrogen synthesis. Second, the LH surge, which occurs in response to a positive feedback effect of estradiol produced from a preovulatory follicle, causes oocyte maturation with resumption of meiosis, oo-cyte release, and a shift in production of ovarian steroids from a predominantly estrogen-producing follicle to a progesterone-producing corpus luteum. The pla-cental gonadotropin, hCG, is produced by the early pregnancy and functions through the same receptor as LH. As a result, it has the same activity as LH, and its primary biological purpose is to continue to support progesterone production by the corpus luteum throughout the first trimester and until the placenta develops. Finally, FSH stimulates ovarian follicle growth and stimulates aromatase activity in granulosa cells. The aromatase activity is responsible for conversion of the LH stimulated androgens from the theca cells into estrogens. While the physiological function of these hormones is to ensure regular, monofollicular ovulation and hormonal support in early pregnancy, these hormones can be used pharmacologically to induce ovulation in women with ovulatory defects or to induce superovulation (e.g., multifollicular development) in ovulatory patients to increase the chance of pregnancy.

The first live birth from gonadotropin therapy occurred in 1962. The gonadotropins were obtained from the purified urine of postmenopausal women. These preparations were termed human menopausal gonadotropins (hMG) and initially contained 5% gonadotropins and numerous urinary protein contaminants. Due to the impurity and batch-to-batch variability of these preparations, mass was not an appropriate indicator of gonadotropin content. As a result, gonadotropin preparations have traditionally been expressed in international units (IU) of activity, as measured by a standard bioassay. Initial hMG preparations contained equivalent amounts of FSH and LH per unit. These preparations were typically administered by intramuscular injection (IM). Years later, a urinary FSH (uFSH) product was developed that had most of the LH activity removed although it still contained significant impurities. The rationale for this was that endogenous LH levels were adequate and that excessive LH activity could be harmful to folliculogenesis. Subsequently, a highly purified urinary FSH (uFSH-HP) was developed. This was >95% pure and offered the advantage of subcutaneous administration with little local irritation. Finally, the end of the last millennium brought the development

of recombinant DNA technology and with it the development of recombinant FSH (rFSH). These products contain exclusively recombinant FSH, >99% pure, without significant batch-to-batch variation. Similarly rLH and rhCG have been developed and are available for clinical use.

While there has been much progress in the development and use of gonadotro-pins, there is a paucity of evidence that any one preparation is clinically superior to another. Two different meta-analyses of several randomized, controlled trials gave different results with respect to pregnancy rates when comparing ovulation induction using FSH to hMG. The initial meta-analysis demonstrated a higher pregnancy rate in when FSH was used for ovarian stimulation for in vitro fertilization. In contrast, a reanalysis of this data with a larger number of studies showed little difference between these two preparations. Most recently, a meta-analysis comparing rFSH to hMG demonstrated no difference in clinical pregnancy rates. While the recombinant preparations are more expensive and at this point, they do not appear to offer any clinical advantage over hMG or uFSH, they have less batch variability, virtually no infectious risk that theoretically exists with urinary preparations, an essentially limitless supply that is not constrained by access to urine from postmenopausal women, and the ability to develop novel ovulation induction regimens with varying doses of rFSH, rLH, and rhCG. For most clinical purposes, any of the FSH or hMG preparations may be used interchangeably.

Multiple pregnancy and OHSS occur with higher frequency in patients treated with gonadotropins. A recent study of over 4000 gonadotropin plus IUI cycles revealed a 14.4% pregnancy rate/cycle, with an overall 25% multiple pregnancy rate, with a higher order multiple pregnancy rate of 6%. OHSS rates can be up to 11% in PCOS patients undergoing gonadotropin ovulation induction.

Follicular Maturation with hCG—The Terminal Act in Ovulation Induction

The purpose of the LH surge is to initiate ovulation, maturation of the oocyte, and development of the corpus luteum. This can occur spontaneously with most types of ovulation induction but is usually brought on pharmacologically in large part for practical reasons. By administering an agent that mimics the LH surge, we are virtually ensure that the events that occur as a result of the LH surge take place, and we can also control the timing of these events. Since the LH surge precedes ovulation by approximately 36 hours, timing of IUI or intercourse may be coordinated with the pharmacologically induced surge.

The most common agent used for follicular maturation is hCG. The structure of hCG is similar to LH, and it acts through the LH receptor to mimic the LH surge. There are both uhCG and rhCG products available. It is typically administered in doses of 5000-10000 IU for uhCG administered IM or SC, or 250 ^g of rhCG administered SC. Both agents are equally effective in ovulation induction. The lower dose of uhCG may lower the risk of OHSS in patients at greatest risk.

While hCG is the most common agent for inducing final follicular maturation, both LH and GnRH agonists may be used. The clinical use of LH for follicular maturation has been limited due to the large dose required for this purpose and its shorter half-life than hCG. GnRH agonists have been also been used, and they hold the advantage of stimulating an endogenous LH surge from the pituitary that is more physiological, potentially lowering the risk of OHSS.

Gonadotropin Ovulation Induction in PCOS

There are numerous protocols for ovulation induction with gonadotropins in PCOS women. The two most common protocols are the low dose step-up protocol and the step-down protocol, both of which are adequate. It has been suggested that the low dose step-up protocol has a lower rate of OHSS and multiple pregnancies, and possibly a higher pregnancy rate. Whatever protocol is used, close ultrasound and estradiol monitoring is essential for avoiding complications.

The step-up protocol is typically started on cycle day 2 or 3 of the menstrual cycle, often after a progestin-induced withdrawal bleed (Fig. 15.2). The initial FSH starting dose is typically 75 IU/day, but has been effective at lower doses. The initial dose is given for 7 days, and ultrasound and estradiol levels are obtained. If follicles >10 mm are seen, the same dose is continued and patients return for ultrasound and estradiol testing every 1-2 days until the lead follicle is >17 mm in diameter. Follicu-lar maturation is then initiated with hCG, but this may be withheld if there are greater than four follicles with >14 mm diameter or estradiol >2000 pg/ml, due to the risk of OHSS and multiple pregnancy. If after 7 days of initial stimulation the follicles are <10 mm, the same dose is continued for another 7 days and ultrasound examination is performed again. If the follicles are >10 mm, then the protocol is continued at the same dose (threshold dose) until a follicle >17 mm is seen. If the follicles remain <10 mm, FSH dose is increased 37.5 IU daily for 7 days, and is increased 37.5 IU every 7 days until a threshold dose is reached.

Low Dose Gonadotropins For Pcos
Figure 15.2. Low dose step-up protocol for gonadotropin ovulation induction. FSH, follicle stimulating hormone; hCG, human chorionic gonadotropin; IUI, intrauterine insemination; IU, international units.

The step-down protocol is started on cycle day 2 or 3 of the menstrual cycle at an FSH starting dose of 150-225 IU/day for 5 days (Fig. 15.3). Ultrasound and estradiol levels are then performed. If follicles >10 mm are seen, the dose is decreased by 37.5 IU every 3 days and the cycle monitored with ultrasound and estradiol every

1-2 days until the lead follicle >17 mm. Follicular maturation is then initiated with hCG unless the risk of OHSS or multiple pregnancy is too great. If after 5 days of initial stimulation, all follicles are <10 mm, the dose is increased by 37.5 IU every

2-3 days and monitored every 2-3 days, for up to 10 days, until follicles >10 mm are seen. At this point, the dose is decreased by 37.5 IU every 3 days until a mature follicle is seen. If there is still no growth after 10 days at the higher dose, the cycle is cancelled and a low dose step-up protocol may be considered.

Ovulation in Hypogonadotropic Hypogonadism

Anovulation of this type, also termed WHO group I anovulation or hypothalamic anovulation, is due to low FSH and LH. As a result, these patients generally require a gonadotropin preparation that contains LH activity. This could be in the form of hMG, rFSH plus rLH, or rFSH plus low-dose rhCG. In hypogonadotropic hypogonadism, estradiol levels remain low in women stimulated with FSH only, due to the absence of LH activity driving ovarian androgen precursor production. In the absence of LH activity, ovulation is significantly diminished. As a result, stimulation protocols must contain LH activity. Ovulation induction for these

Ovulation Stimulation
Figure 15.3. Step-down protocol for gonadotropin ovulation induction. FSH, Follicle stimulating hormone; hCG, Human chorionic gonadotropin; IUI, Intrauterine insemination; IU, International units.

patients may be performed using either hMG or rFSH plus 75 IU rLH daily. Risk of OHSS and multifollicular development is lower than in WHO group II anovula-tion. As a result, increased doses of gonadotropins may be used.

Ovulation induction is usually started with a dose of 75-225 IU/day of hMG or 75-225 IU/day rFSH plus 75 IU/day of rLH, for 5 days. Ultrasound and estradiol monitoring are performed after 5 days, and dose adjustments of hMG or rFSH may be increased or decreased by 75 IU/day, depending on the adequacy of response. This is continued until the lead follicle reaches at least 17 mm. Follicular maturation is then initiated with hCG unless the risk of OHSS or multiple pregnancy is excessive.

Gonadotropins in Controlled Ovarian Hyperstimulation (COH)

Gonadotropins may be used in regularly ovulating women in order to increase their fecundability. Gonadotropin therapy is often used in conjunction with IUI in patients with unexplained infertility, mild male-factor infertility, and mild/ moderate endometriosis, with improved pregnancy rates. In women with endometriosis, gonadotropin treatment with IUI resulted in a 5-fold increase in pregnancy rates when compared to no treatment. In unexplained or male-factor infertility, gonadotropin treatment with IUI resulted in a 1.7-fold increase in pregnancy rates when compared to IUI alone. Controlled ovarian hyperstimulation is often performed with a fixed-dose protocol, starting stimulation on cycle day 3 at an FSH or hMG dose of 150-225 IU/day for 5 days. Ultrasound and estradiol monitoring is then performed every 1-2 days once a follicle >10 mm is identified. Criteria for follicular maturation with hCG are identical to other ovulation induction protocols, and the same caution for OHSS and multiple pregnancy risks must be observed.

COH with Gonadotropins in in Vitro Fertilization (IVF)

Gonadotropin stimulation is the mainstay of COH in IVF. The purpose of COH in IVF stimulation is to produce multiple follicles for transvaginal oocyte retrieval, in vitro fertilization of oocytes, and subsequent transfer of 1-3 embryos into the uterus after 3-5 days of in vitro embryo culture. The details of these protocols extend beyond the scope of this chapter.

Key Points

1. Ovulation induction remains a mainstay of infertility treatment of women with ovulatory disorders.

2. Weight loss and clomiphene citrate ± metformin are the first-line ovulation induction methods in PCOS women.

3. Gonadotropins are first-line for anovulation due to hypogonadotropic hy-pogonadism and are second-line therapy for PCOS.

4. The major risks of ovulation induction are OHSS and multiple pregnancy. These risks can be reduced with appropriate monitoring.

5. Future directions in ovulation induction will be directed at greater individu-alization of protocols to increase pregnancy rates and decrease multiple births through monofollicular ovulation.

Suggested Reading

1. Dickey RP, Taylor SN, Lu PY et al. Risk factors for high-order multiple pregnancy and multiple birth after controlled ovarian hyperstimulation: results of 4,062 intrauterine insemination cycles. Fertil Steril 2005;83:671-83, [A large review of the risk factors for higher order multiple pregnancy in gonadotropin ovulation induction].

2. Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod 2004;19:2474-83, [A review of the role of pregnancy and ovulatory rates in ovulation induction protocols using metformin].

3. Guzick DS, Carson SA, Coutifaris C et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network. N Engl J Med 1999;340:177-83, [A randomized controlled trial examining the pregnancy rates in COH ± IUI in patients with unexplained and mild male-factor infertility].

4. Dunson DB, Baird DD, Wilcox AJ et al. Day-specific probabilities of clinical pregnancy based on two studies with imperfect measures of ovulation. Hum Reprod 1999; 14:1835-1839.

5. Farquhar C, Vandekerckhove P, Lilford R. Laparoscopic "drilling" by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev 2001; CD001122.

6. Filicori M, Flamigni C, Dellai P et al. Treatment of anovulation with pulsatile gonadotropin-releasing hormone: Prognostic factors and clinical results in 600 cycles. J Clin Endocrinol Metab 1994; 79:1215-1220.

7. Haas DA, Carr BR, Attia GR. Effects of metformin on body mass index, menstrual cyclicity, and ovulation induction in women with polycystic ovary syndrome. Fertil Steril 2003; 79:469-481.

8. Homburg R, Howles CM. Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: Rationale, results, reflections and refinements. Hum Reprod Update1999; 5:493-499.

9. Mitwally MF, Casper RF. Aromatase inhibitors in ovulation induction. Semin Reprod Med 2004; 22:61-78.

10. Randall JM, Templeton A. Transvaginal sonographic assessment of follicular and en-dometrial growth in spontaneous and clomiphene citrate cycles. Fertil Steril 1991; 56:208-212.

11. van Santbrink EJ, Hop WC, van Dessel TJ et al. Decremental follicle-stimulating hormone and dominant follicle development during the normal menstrual cycle. Fertil Steril 1995; 64:37-43.

12. van Wely M, Westergaard LG, Bossuyt PM et al. Human menopausal gonadotropin versus recombinant follicle stimulation hormone for ovarian stimulation in assisted reproductive cycles. Cochrane Database Syst Rev 2003; CD003973.

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  • Gorbadoc
    WHO classification of ovulation disorders VI?
    3 years ago

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