KatCarney

Treatment of Oligo/Amenorrhea and Infertility

Chronic oligo/anovulation results in persistent stimulation of endometrial tissue by estrogen (mainly estrone). In the setting of PCOS, without the progesterone-induced inhibition of proliferation and differentiation to secretory endometrium that occurs after ovulation, there is an increased risk for endometrial hyperplasia and carcinoma.[22] A threefold increased risk of endometrial cancer in anovulatory women has been reported.[23] Although 5% or fewer of endometrial cancers occur in women under the age of 40 years, the majority have PCOS.[24] Thus, anovulatory women with PCOS are recommended to take progestins to reduce the risk of endometrial hyperplasia or carcinoma.

An endometrial biopsy is suggested if a patient has been anovulatory for a year or more;[25] ultrasonography may help to establish risk and need for biopsy. If a progestin is used, it should be given for 12 to 14 days every month to minimize the risk of endometrial hyperplasia.[26,27] The combined estrogen-progestin oral contraceptive pill is particularly beneficial in women with PCOS in that it both inhibits endometrial proliferation and reduces ovarian androgen production, thus ameliorating the consequences of hyperandrogenism.

Clomiphene citrate remains the first line of therapy for ovulation induction in women with PCOS.[28,29] The usual regimen is 50 mg/day for 5 days beginning on cycle day 3 to 5 following spontaneous or progestin-induced bleeding. The dose can be increased by 50 mg per day (usually to a maximum dose of 200 mg/day) in subsequent cycles if ovulation does not occur (serum progesterone in the luteal phase remains less than 3 ng/mL). Using a graduated regimen of 50 to 200 mg daily for 5 days, ovulation can be induced in about 80% of oligomenorrheic women, of whom approximately half conceive. In women without other infertility factors, about 88% of those ovulating eventually conceive with a monthly fecundity rate of 0.22, which is similar to that of fertile women discontinuing the diaphragm.[30] There is a 15% spontaneous abortion rate and a 4% incidence of twins[30,31] associated with the use of clomiphene citrate. Metformin has been reported to reduce the rate of spontaneous pregnancy loss in PCOS (see later).[32]

The PCOS patients who do not respond to clomiphene therapy usually require either low-dose human recombinant follicle-stimulating hormone (FSH) or surgically induced ovulation (i.e., ovarian diathermy). In hyperinsulinemic women with PCOS, lowering insulin levels with either drugs or weight loss may also induce ovulation (see later).

There is no clinical advantage of human menopausal gonadotropins (hMGs) over FSH for induction of ovulation in women with PCOS.[33] In PCOS, stimulation is initiated with 75 IU/day instead of the standard 150 IU, and patients are maintained on this dose for 1 to 2 weeks. This lower dose lowers the risk of ovarian hyperstimulation syndrome. Gonadotropins are increased at 0.5 ampule increments (37.5 IU) every 7 days if no follicular growth occurs at the initial dose as determined by ultrasonography. Compared with standard gonadotropin therapy, low-dose therapy with either FSH or hMG in PCOS results in a higher rate of single dominant follicle development, fewer ovulatory follicles at the time of human chorionic gonadotropin administration, and lower mean estradiol levels.[34-38] Reducing the FSH dose as follicular size increases may further increase the likelihood of monofollicular development.[39,40]

With low-dose gonadotropin therapy about 95% of patients ovulate with a 55% cumulative pregnancy rate after six cycles.[41] Multiple gestation occurs in only 6% of pregnancies. However, spontaneous abortion rates range from 20 to 35%.[37,41] Down-regulating the pituitary-ovarian axis with GnRH agonist prior to initiation of gonadotropin therapy may decrease the likelihood of spontaneous abortion,[42,43] but this has never been confirmed in a randomized trial.

There has been renewed interest in surgically inducing ovulation in women with PCOS using laparoscopy and electrocautery or laser to produce multiple burns in the ovarian capsule. A review of 1124 patients found spontaneous ovulation in 77% and pregnancy in 49% of patients.[44] Most patients ovulated spontaneously following laparoscopic ovulation induction, but some required clomiphene citrate or gonadotropins, which increased the total pregnancy rate to 60%. In PCOS patients with only anovulation and no other infertility factors, a cumulative pregnancy rate of 80%, with about 80% of conceptions occurring within the first 8 months after surgery, has been reported.[45] In contrast to results with gonadotropins, the spontaneous abortion rate after a laparoscopic ovulation induction is only about 15% and multiple pregnancies are uncommon (2.5%).[44,46]

As noted, lowering insulin levels with either weight loss or drugs may induce ovulation in obese, hyperinsulinemic women with PCOS. A modest weight loss of 5 to 10% results in return to regular menses or pregnancy in up to 80% of obese women with PCOS.[29,47] Both metformin and troglitazone have been reported to restore regular menses and induce ovulation in women with PCOS.[48-50] In a randomized trial, obese women with PCOS were significantly more likely to ovulate if they received 1500 mg of metformin daily (34%) rather than placebo (4%; p < 0.001) for 35 days.[51] Of the subjects who remained anovulatory after 35 days, the metformin-treated subjects were significantly more likely to ovulate following clomiphene treatment than the placebo-treated subjects (90 versus 8%; p < 0.001). When troglitazone was administered to women with PCOS either alone or in conjunction with clomiphene citrate, there was a significant enhancement in ovulatory function.[49] Specifically, the ovulation rate per cycle increased from 34.9% with clomiphene citrate alone to 72.7% when troglitazone was coadministered.

Finally, a multicenter study[50] in which 305 premenopausal women with PCOS were randomly assigned to treatment with placebo (PBO) or troglitazone (150, 300, or 600 mg/day) revealed that ovulatory rates were significantly greater for patients receiving 300 and 600 mg than for those receiving placebo. Of PCOS patients treated with 600 mg, 57% ovulated over 50% of the time compared with 12% of placebo-treated patients. Thus, troglitazone improved the ovulatory dysfunction of PCOS in a dose-related fashion, with a minimum of adverse effects. Although ovulation induction with insulin-lowering therapy has been promising, especially in obese PCOS patients, pregnancy rates and long-term outcomes with such agents remain unknown.

http://www.medscape.com/viewarticle/466019_print

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