Fig. 16.1
Laparoscopic image of polycystic ovaries after transvaginal oocyte collection
16.2.3 WHO Group III: Hypergonadotropic Anovulation
This group includes women with elevated level of gonadotropins such as follicle stimulating hormone (FSH) and low or normal estradiol level. Typically, it is associated with amenorrhea, and accounts for about 10–20% of ovulatory disorders. Examples include idiopathic premature ovarian failure (POF), as well as POF related to underlying conditions, such as Turner Syndrome and Fragile X carriers. Iatrogenic POF after treatment with gonadotoxic substances such as chemotherapy or pelvic radiation therapy is also included in this group.
An additional cause of anovulation that is not included in the above classification, but is sometimes considered a fourth group, is hyperprolactinemia. High prolactin level inhibits gonadotropin secretion and results in oligo or amenorrhea. Investigations and treatment of hyperprolactinemia is discussed in a different chapter .
16.3 Treatments for Ovulatory Disorders
Various options are available for the treatment of ovulatory disorders. The choice of treatment depends on the underlying cause of anovulation. A thorough history and physical examination of both partners should be first performed to rule out any underlying pathologies and determine the best course of action. As a general rule, the least invasive options with fewer side effects are used first and more invasive treatments with higher risks kept as a last resort. Interventions can be as simple as weight loss and exercise, followed by oral agents such as clomiphene citrate or aromatase inhibitors, with or without insulin-sensitizing agents. More aggressive therapies include gonadotropins injections. With the availability of in-vitro fertilization, surgery such as laparoscopic ovarian drilling or wedge resection has become outdated.
16.4 Lifestyle and Exercise
Metabolic syndrome and high body mass index is associated with anovulation, often due to polycystic ovarian syndrome (PCOS ). PCOS is associated with insulin resistance, hyperandrogenism, oligo or amenorrhea and polycystic ovarian morphology on ultrasound. It is a very common cause of secondary amenorrhea in reproductive age female. There is good evidence that in overweight patient, lifestyle modifications including diet and exercise leading to weight loss can lead to spontaneous return of ovulation. The serum levels of testosterone and insulin decrease after weight loss in obese-PCOS women [1]. Clinical signs of hyperandrogenism such as hirsutism and acne subsequently improve [2]. In fact, weight loss by diet and exercise alone can lead to resumption of ovulation in overweight patients presenting with PCOS [3].
Another important aspect to consider in such patients is pregnancy-related morbidity including gestational diabetes, preeclampsia, hypertension, cesarean delivery and postpartum weight retention. Fetal and child morbidity and mortality are also more prevalent due to increased stillbirth, prematurity, congenital anomalies, macrosomia leading to possible birth injury and childhood obesity. Due to obesity, these patients might have difficulties with anesthesia during labor and increased wound infection. Initiation and sustainment of breastfeeding is also less likely in obese mothers [4].
The first line of treatment for overweight anovulatory women desiring pregnancy is therefore weight loss and exercise. It often leads to spontaneous resumption of ovulation and provides future mothers with the opportunity for a healthier pregnancy with less risk of complications.
16.5 Clomiphene Citrate
Clomiphene citrate is the first agent used for ovulation induction, first described in the 1950s [5]. It is given orally and cleared through the liver and then excreted in the stool. About 85% of a dose is eliminated after 6 days, however traces can remain in the circulation for much longer.
16.5.1 Pharmacology and Mechanism of Action
It is a selective estrogen receptor modulator (SERM) which acts as an agonist or antagonist on the estrogen receptors, depending on the target tissue. The currently manufactured product is a mixture of two isomers, in an approximate 3:2 ratio of enclomiphene and zuclomiphene. Enclomiphene seems to be the most potent isomer of the two, and the one responsible for the ovulation induction effect. It is usually cleared more rapidly than zuclomiphene , which does not seem to have any clinical relevance [6].
The mechanism of action of clomiphene citrate is believed to happen at the level of the hypothalamus, where it binds to the estrogen receptors and depletes its concentration by interfering with the normal replenishing mechanism. This depletion of estrogen receptor is viewed by the hypothalamus as low circulating estrogen. It then triggers an alteration in GnRH pulsatility resulting in an increase of circulating gonadotropins stimulating the ovary. The subsequent increase in circulating levels of FSH and LH stimulates folliculogenesis and ovulation. It is expected to occur 5–12 days after clomiphene citrate administration [6].
16.5.2 Dosage and Administration
The usual starting dose of clomiphene citrate is 50–100 mg orally every day, for 5 days, starting on day 2–5 of the menstrual or induced cycle. The standard effective dose of CC ranges from 50 to 250 mg/days, although doses in excess of 100 mg/days are not recommended by the US Food and Drug Administration (FDA) and seem to add little to clinical pregnancy rates [6]. Response can be evaluated by ultrasound examination around day 10 of the cycle to view and measure the developing follicle. Urinary LH kits can also be used at midcycle to detect the presence of ovulation. A spontaneous menses at the expected timing of the cycle is also indicative of ovulation .
16.5.3 Side Effects and Risks
In general, clomiphene citrate is well tolerated. Common side effects include mood swings and hot flushes, but are rarely persistent or severe enough to discontinue the treatment. These side effects are temporary and short lived. Visual symptoms such as blurred or double vision, scotomata, and light sensitivity are rare and reversible. Yet, there have been reports of persistent visual symptoms and severe complication such as optic neuropathy [7]. If such visual disturbances occur, CC should be discontinued. Other less specific side effects include pelvic discomfort, breast tenderness, and nausea, observed in 2–5% of patients treated with clomiphene citrate [6].
Treatment with CC is associated with the risks of multiple pregnancies and rarely ovarian hyperstimulation syndrome (OHSS). Multiple pregnancies are due to multifollicular development, and usually results in twin pregnancies. The rate of twin pregnancies is around 8% in anovulatory women and 2.6–7.4% in those with unexplained infertility. The rate of high order multiple pregnancy is much lower (0.08–1.1%) [6]. Ovarian hyperstimulation syndrome rarely occurs with CC. There is no good evidence that the use of clomiphene citrate per se increases the risk of miscarriage, congenital malformations, or ovarian cancer [6].
However, clomiphene citrate can have a negative effect on estrogen responsive tissue such as the endometrium and the cervix. It can result in a thin endometrium and luteal phase defect [8]. Ovulation trigger with hCG or progesterone supplementation may improve the luteal phase. Strategies to avoid a thin endometrium include starting clomiphene citrate on day 1 of the cycle , lowering the dose to 25 mg daily, or supplementation with exogenous estrogen near the time of ovulation [9].
16.5.4 Effectiveness
About 75–80% of patients with PCOS will ovulate with clomiphene citrate treatment. The conception rate per cycle in ovulatory women after clomiphene citrate treatment is up to 22% [10]. Over a half of the patients will ovulate with 50 mg daily dose. Those who do not ovulate with 50 mg may ovulate at higher doses using a step-up regimen with doses escalation by 50 mg with each anovulatory cycle (22% with 100 mg, 12% with 150 mg, 7% with 200 mg, and 5% with 250 mg). Higher doses sometimes required in patients with increased BMI [6].
16.6 Aromatase Inhibitors
Aromatase inhibitors were first developed to lower estrogen levels in the context of breast cancer treatments. The application of this medication for ovulation induction in WHO Group II anovulatory patients, mainly in PCOS was first described in 2001 [11].
16.6.1 Pharmacology and Mechanism of Action
This compound is a cytochrome P450 inhibitor of the aromatase enzyme complex, which results in downregulation of estrogen production. Lower circulating estrogen levels inhibit the negative feedback loop to the hypothalamus, which results in stronger GnRH pulses release. This further stimulates the pituitary gland to produce more FSH, which induces development of follicles in the ovaries.
The lack of depletion of estrogen receptors by aromatase inhibitors offers a few potential advantages over clomiphene citrate. First, because the estrogen receptors are intact at the level of the hypothalamus, the normal negative feedback loop is also intact. As the growing dominant follicle produces more estrogen, it leads to normal atresia of the smaller follicles and produces monofollicular growth and lower risk of multiple pregnancy. Aromatase inhibitors have less anti-estrogenic effect on the endometrium and cervix than clomiphene citrate [12].
The most commonly use aromatase inhibitor for ovulation induction is its third generation, such as letrozole. It has a relatively short half life of 45 h, offering the advantage of being cleared from the system rapidly, often even before conception occur, therefore limiting the exposure of the potential early pregnancy [13].
16.6.2 Dosage and Administration
16.6.3 Side Effects and Risks
Despite growing evidence for its effectiveness and safety, FDA and Health Canada do not approve its use for ovulation induction. The concern about congenital malformations in offspring born after letrozole treatment is unfounded [3, 12, 15]. In general, side effects of letrozole use for ovulation induction are mild and limited. These include hot flushes, dizziness, and fatigue [3].
The risk of multiple pregnancy with letrozole is lower than that with clomiphene citrate. In a randomized trial, the multiple pregnancy rate after letrozole was 3.4% versus 7.4% in the clomiphene citrate group [3].
16.6.4 Effectiveness
In a recent randomized study, the cumulative live birth rates were significantly higher at 27.5% in the letrozole group and 19.1% in the clomiphene group (relative risk [RR] 1.44, 95% CI 1.10–1.87). The cumulative ovulation rate was also higher with letrozole, at 62% versus 48% with clomiphene citrate (RR 1.28, 95% CI 1.19–1.37) [16]. A Cochrane review on the subject reported a higher live birth rate with letrozole (275 per 1000) than with clomiphene (188 per 1000) and a higher clinical pregnancy rate (262 per 1000 for letrozole and 202 per 1000 for clomiphene). The miscarriage rates were similar between the two groups (123 per 1000 for letrozole and 134 per 1000 for clomiphene). There was no case of OHSS reported in any of the above-mentioned study [12].
Letrozole is as effective as and maybe more effective than clomiphene citrate for ovulation induction in PCOS patients. However, patients should be informed of the risks and benefits of both options, and be aware that letrozole use is off label for such indication .
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