There’s hope in treating polycystic ovary syndrome

Therapies help insulin-resistant women ovulate

The 38-year-old Scottish patient of Luigi Mastroianni, MD, is thriving and so is her 1-year-old daughter. For Mastroianni, professor of obstetrics and gynecology at the University of Pennsylvania Medical Center in Philadelphia, the woman’s pregnancy was almost as simple as lowering her blood glucose.

The patient had polycystic ovary syndrome (PCOS), a disease closely linked to insulin intolerance, and she was not ovulating. After her first baby was conceived in vitro, she wanted to try the procedure for a second child. Mastroianni told her it didn’t need to be that complicated. "I got her to lose ten pounds and take 1,000 mg of glucophage a day and got her fasting blood glucose down to between 70 and 105. In a few months, she had a spontaneous menstrual period and after four or five periods, she became pregnant. We’re just learning on the job," he says.

PCOS is a disease that can leave women hirsute, acne-scarred, obese, and unable to conceive in more than 60% of the cases. The disease is compounded by the psychological impact of the physical appearance of the typical sufferer and her inability to become pregnant.

Beyond that, says John E. Nestler, MD, professor and chair of the department of endocrinology at the Medical College of Virginia in Richmond, 30% of the women who develop PCOS, usually in their teen-age years, will develop Type 2 diabetes by the age of 30. They are also at risk for hypertension, dislipidemia, elevated cholesterol, and cardiovascular disease.

"PCOS has the same underlying disease pattern as diabetes, and it affects 6% to 10% of women of childbearing age," says Nestler. "It’s a metabolic disorder that may be the most serious disorder in young women." The face of PCOS is changing, he adds. Now, increasingly, researchers are finding that drugs that work for diabetes are also effective treatments for PCOS. In addition to Mastroianni’s positive results with glucophage, Nestler has worked with a drug still in the pre-clinical trials stage, and researchers at the West Virginia University Health Sciences Center have had good results with thiazolidinediones.

Rezulin had a powerful effect in producing ovulation in women who were resistant to all other therapies, according to researchers at West Virginia University School of Medicine in Charleston. Troglitazone alone, or used with clomiphene, produced ovulation in 15 of 18 patients (83%), and seven of them became pregnant during the study.

Tamer Yalcinkaya, MD, the university’s chief of reproductive endocrinology and infertility, says the results were particularly exciting because the study subjects had been resistant to all other types of therapy. "Insulin sensitizing agents like all the thiazolidinediones and metformin may revolutionize the treatment of PCOS by tackling one of the underlying causes of the disease. In the past, we’ve only been able to treat symptoms."

In a study now under way, Yalcinkaya’s team is using rosiglitazone, and preliminary results are similar to those for troglitazone. No participants in the troglitazone study suffered any adverse liver effects, he says. (See article on Rezulin, p. 13.) Metformin and clomiphene have been used successfully in women with PCOS in other studies, he notes.

Nestler’s study shows the promise of the phosphoglycan d-chiro-inositol in treating PCOS. His team worked on the theory that treating the insulin resistance and hyperinsulinemia in women with PCOS would restore concentrations of the mediator and improve insulin sensitivity. Not only did the substance significantly improve ovulatory function in the 22 women with PCOS, Nestler’s group found significant improvement in insulin sensitivity; they found reduced blood pressure and plasma triglyceride concentrations.

D-chiro-inositol, being developed at INS-1 by INSMED Pharmaceuticals of Richmond, VA, has completed Phase 2 clinical trials, and company officials expect Phase 3 trials soon.

Until d-chiro-inositol becomes commercially available, Nestler says metformin is his drug of choice for treating PCOS, although he predicts "over the next couple of years, insulin, sensitizing-drugs will become the first line of treatment for PCOS."

"PCOS is the most common cause of ovulatory failure," says Mastroianni, so clinicians should consider the possibility of the disease even in very young women with irregular menstrual periods a year after menarche.

In fact, PCOS identified very early and treated early may stave off some of the psychological effects of the disease. Researchers even dare to theorize that it might reduce the risk of developing Type 2 diabetes, although no studies have been done on that subject.

Any woman who has eight or fewer menstrual periods a year should be evaluated for PCOS, says Nestler. "They shouldn’t accept any curt assurances. They should get a complete work-up."

Yalcinkaya suggests the following treatments for women with PCOS:

• Consider low dose oral contraceptives.

• Encourage the patient to lose weight if she is overweight.

• Consider anti-androgens.

• Consider oral agents like thiazolidenediones and metformin, which will improve insulin sensitivity and might even help weight loss.

Emotional support is key to treating women with PCOS, Yalcinkaya adds. "It’s important to explain to them the pathophysiology of the disease and help relieve anxiety. There is something we can do about this."

Psychological counseling may be necessary, he adds. Patients have a wide variety of fears with this disease and are particularly fearful they will grow a beard, they won’t be attractive because of facial scarring, or they will need a hysterectomy. "Many of them regard themselves as freaks," says Nestler. "It helps tremendously to let them know this is a treatable disorder. Often doctors are not very helpful or don’t explain enough."

And the availability of insulin sensitizers for PCOS is giving them hope for normal lives and normal pregnancies. "That’s very promising," Nestler says.

[Contact Luigi Mastroianni at (215) 662-2970, John Nestler at (804) 62809696, and Tamer Yalcinkaya at (304) 388-1515.]