NIH vs. RCC vs. AES criteria for PCOS.
This chapter will cover the office management of infertility secondary to ovulatory problems. Complication of ovarian hyperstimulation will also be described.
The goal of primary treatment for patients presenting with anovulation and infertility is restoration of the normal ovarian physiology that results in selection of a single dominant follicle and subsequent mono-ovulation. The treatment is usually referred to as ovulation induction. The ovarian stimulation that is used in assisted conception such as in vitro fertilization or intrauterine insemination is usually referred to as controlled ovarian hyperstimulation.
Lifestyle modification
Lifestyle modifications such as overweight reduction, exercise, and smoking cessation are recommended. These interventions may improve insulin sensitivity and decrease androgen excess, which therefore normalizes the patient’s endocrinology.
Weight reduction
Permanent weight reduction may lead to ovulation and subsequent pregnancy. A wide array of treatment strategies has been used to achieve weight reduction including behavioral counseling lifestyle, therapy pharmacological treatment and bariatric surgery (see Chapter 39). No randomized trials compare these treatments benefits in the area of infertility management. Fertility guidelines in some European countries recommend withholding treatment in all obese women with a body mass index (BMI) above 35 kg/m2 until weight is normalized.[3, 4] Women who are overweight benefit from reduction of the glycemic load by alleviating hyperinsulinemia and its metabolic consequences.[5] The effect of different diets on PCOS patients has been studied in two randomized control trials.[6, 7] Neither specific type was superior to the other in weight loss and outcome.
Exercise
The combination of diet and exercise has proven efficacy;[8] there are no available studies that evaluate exercise alone.
Smoking cessation
Smoking accelerates follicular depletion and increases serum FSH concentrations in young smokers versus nonsmokers. Smoking may also increase spontaneous miscarriage and ectopic pregnancy. Every effort should be made to encourage patient before fertility treatment is started (see Chapter 40).
Ovulation induction in hypogonadotropic hypogonadism
Anovulation in hypogonadotrpic hypogonadism results from hypothalamic-pituitary problems. A gonadotropin-releasing hormone (GnRH) stimulation test can make the distinction between pituitary and hypothalamic etiologies. The administration of GnRH agonist will be successful in increasing the serum gonadotropins only if the pituitary gland is functional. If anovulation is related to significant weight loss, restoration of the normal weight will eventually result in return of regular ovulatory cycles.[9] A pulsatile GnRH agonist pump could achieve safe and successful outcomes in patients with functional pituitary problems. The use of the pulsatile pump restores the secretion of LH and FSH, which in turn will induce ovarian induction. If no pregnancy occurs after using the GnRH agonist pump, the next step is stimulation with gonadotropins for follicular growth and ovulation. After conception, luteal phase support using human chorionic gonadotropin or progesterone should be considered until HCG production is provided by the pregnancy.[10]
Ovulation induction in normogonadotropic induction
Multiple options exist for the treatment of anovulatory infertility patients with normogonadotropic laboratory findings. Medications include clomiphene citrate, tamoxifen, metformin, aromatase inhibitors and gonadotropins as will be discussed. Typically, anovulatory polycystic ovarian patients are started on clomiphene citrate as first line. If treatment fails or is resistant to clomiphene citrate, gonadotropins are to be used (Figure 27-2).
Treatment of anovulatory polycystic ovarian patients.
Anti-estrogens
Clomiphene citrate
Clomiphene citrate has been the first line treatment of anovulation since the early 1930s, as this medication is effective, safe, and inexpensive.[11]
Mechanism of action
Clomiphene citrate is a nonselective estrogen receptor antagonist that interferes with the endogenous estrogen feedback in the hypothalamic-pituitary level. Gonadotropin released by the pituitary gland is enhanced and ovarian stimulation follows.
Plan of treatment
Clomiphene citrate is started on day 3 of the menstrual cycle whether it starts spontaneously or after progesterone withdrawal. Typically the starting dose of clomiphene citrate is 50 mg/day for five days. If the patient fails to ovulate, the dose will be increased to a maximum of 150 mg/day. The starting day of clomiphene citrate has varied between the United States and Europe. When clomiphene citrate treatment was started on day 5 instead of day 1, ovulation rate and pregnancy rate were lower.[12] Routine addition of metformin to clomiphene citrate does not increase pregnancy rate.[13, 14] Also, routine addition of dexamethasone to clomiphene citrate does not increase the pregnancy rate. Estrogen vaginal cream may be useful if the endometrium is thin during the follicular phase and vaginal progesterone gel may be added when necessary.
Outcome of treatment
Ovulation is restored in approximately 80% of anovulatory patients and cumulative live births vary from 40% to 60%.[15, 16] Most pregnancies occur in the first six ovulatory cycles. Continuation of treatment to more than six cycles yields very low success.
Complications
Hot flashes and nausea may occur but are uncommon side effects. Visual problems occur in 1.5% of patients. Multiple follicular developments occur in 2%–10% of cycles. The use of clomiphene citrate for longer than 10 months has been considered a potential risk factor for ovarian cancer.[17] Severe ovarian hyperstimulation syndrome has not been reported after the use of clomiphene citrate by the preceding protocol.[18] The rate of twinning is approximately 6%.
Tamoxifen citrate
Tamoxifen is less commonly used than clomiphene citrate for ovulation induction and is not licensed by the manufacturer for the indication of ovulation induction. It has less anti-estrogenic effect on the endometrium and cervical mucus.[19]
Mechanism of action
Tamoxifen is a nonselective estrogen receptor modulator that is widely used in breast cancer treatment.
Plan of treatment
Tamoxifen is typically started on day 3 of menstrual bleeding at a dose of 20 mg/day and continued for five days. If anovulation persists, it may be increased to 40 mg/day then to 60 mg/day. In a prospective randomized controlled trial, comparing clomiphene citrate and tamoxifen citrate showed no significant change in the pregnancy rate.
Metformin
Metformin may normalize ovarian response to FSH and promote ovulation by lowering insulin resistance and hyperandrogenism.[20]
Mechanism of action
Metformin is an insulin sensitizer that reduces hepatic gluconeogenesis and insulin concentrations. It is currently used to treat patients with diabetes. Insulin resistance plays an important role in the pathogenesis of anovulation in PCOS patients. Hyperinsulinemia increases ovarian androgen production and at the same time decreases sex hormone binding globulin serum concentration. The net effect is an increased bioavailability of androgens.[21] Further more, hyperinsulinemia promotes excessive estrogen response during ovarian stimulation, which induces an early drop in the FSH.[22] This may cause follicle growth arrest in the early follicular phase showing the classic polycystic appearance of the ovaries on ultrasonography.[20]. Metformin therefore reduces these effects of hyperinsulinemia.
Plan of treatment
Metformin is started with two or three tablets of 500 mg to a maximum daily dose of 5,000 mg/day.
Outcome of treatment
First-line treatment using metformin is not superior to clomiphene citrate.[13, 23, 24] Furthermore, routine combined use of metformin and clomiphene citrate is not superior to clomiphene citrate alone. But, for second-line treatment of patients presenting with clomiphene citrate resistant anovulation and a BMI more than 35 kg/m2, Legro, et al. found that the addition of metformin to clomiphene citrate results in 50% ovulation rate.[14] Therefore the use of metformin is recommended in patients with documented glucose intolerance.[20]
Complications
Common side effects are gastrointestinal complaints such as nausea, vomiting, and diarrhea. Lactic acidosis is very rare and has only been reported in patients with renal insufficiency or liver disease. Metformin may reduce the risk of gestational diabetes and may be safe during pregnancy.[25]
Aromatase inhibitors
Aromatase inhibitors block estrogen synthesis in the ovary and therefore stimulate gonadotropin release. They are widely used for the treatment of breast cancer. Aromatase inhibitors do not have an anti-estrogen effect on endometrium and uterus as is seen with clomiphene citrate. Inhibition of aromatase enzyme activity in granulosa cells decreases the conversion of androgen to estrogen and stops the negative feedback of estrogen on the hypothalamic-pituitary pathway.[26]
Mechanism of action
Aromatase inhibitors such as letrozole are typically started on day 3 of the menstrual cycle at a dose of 2.5 mg–5 mg/day and continued for five days.
Outcome of treatment
In a prospective randomized control trial comparing clomiphene citrate 100 mg/day and letrozole 2.5 mg/day in 74 PCOS patients, similar ovulation pregnancy rates were reported.[27]
Complications
Tulandi, et al. reported no difference of congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate.[28] This large trial from Canada contrasts with a small study, also from Canada, on 150 babies following treatment with letrozole demonstrating potential cardiac malformations. The second study was an oral presentation at the American Society for Reproductive Medicine annual meeting in Canada that resulted in an official warning by the manufacturer Novartis Pharmaceutical that letrozole should not be used for ovulation induction.
Gonadotropin
Patients who fail to conceive with clomiphene citrate and letrozole, or patients who are resistant to clomiphene citrate may benefit from gonadotropins (Figure 27-2). Gonadotropins are glycoproteins composed of alpha and beta subunits (Figure 27-3). The glycosylation of the gonadotropins secreted by the pituitary gland vary among women of different ages and also during different times within the menstrual cycle (Figure 27-4). They have been used since the early 1960s. Initially, gonadotropins were extracted from urine of postmenopausal women, and then the urine proteins were removed which resulted in highly purified gonadotropins (Figure 27-5). FSH was then purified alone (Figure 27-6). The large number of postmenopausal women required for the extraction process, combined with the increased demand worldwide, stimulated research in an effort to produce recombinant FSH. Modern recombinant preparations improved purity, consistency and at the same time lead to less variability. Recombinant FSH has now been used worldwide for the last decade even though pregnancy outcomes are comparable between the urinary and recombinant FSH.[29]
Gonadotropin composition.
Human FSH is a mix of isoforms.
Purified gonadotropins.
Highly purified FSH and recombinant FSH.
Mechanism of action
Follicle-stimulating hormone stimulates follicular growth in ovaries. Luteinizing hormone accomplishes the resumption of meiosis. In the ovarian theca cells, the LH promotes the conversion of cholesterol to androstenedione and testosterone. Follicle-stimulating hormone then induces aromatization of these androgens in granulosa cells to estrone and estradiol, respectively. The use of gonadotropins in an anovulatory patient therefore promotes the development of follicles mainly by the FSH followed by the release of the oocytes and resumption of meiosis mainly by the LH. The two hormones work in synergy to achieve the goal of ovulation in anovulatory patients or controlled superovulation in assisted reproduction. Human chorionic gonadotropin is used in place of LH to trigger ovulation (Figure 27-7).
Human chorionic gonadotropin.
Plan of treatment
Van Santbrink and Fauser discussed the two main protocols for ovarian stimulation, namely step-up and step-down protocol (Figure 27-8).[20] The step-up protocol is aimed at increasing low FSH doses by small increments of 37.5 IU/day until the FSH threshold is surpassed resulting in continued follicular growth and ovulation. In contrast, the step-down protocol is aimed at starting a dose of FSH that is equal to the response dose,[20] and then the daily FHS dose may be decreased to 37.5 UI/day resulting in development of a single dominant follicle. Van Santbrink and Fauser noted that whereas the step-down protocol mimics the physiologic serum FSH response, the dominant follicle dose develops more quickly resulting in less ovarian hyper response and cancellation. They recommend the termination of the individual FSH dose using a step-up protocol and then consecutive treatment cycles may be performed according to the step-down protocol.[20] In case the starting dose is equal to the response dose; a fixed dose regimen could be utilized. Monitoring is performed using ultrasound and serum estradiol (Figures 27-9 and 27-10). Human chorionic gonadotropin can then be used to trigger ovulation when at least one follicle is 16 mm–18 mm in diameter. Cancellation is recommended if more than three follicles are larger than 14 mm (Figure 27-11). Luteal phase may be supported with progesterone (Figure 27-12).
