Early Use of Triple Drug Cocktail Improves Ovulation in PCOS

Early intervention with a combination of antiandrogen and insulin-sensitizing agents in adolescents with polycystic ovary syndrome (PCOS) may help improve their fertility and overall health later on, a small new study suggests.

The findings were presented April 4 here at ENDO 2017: The Endocrine Society Annual Meeting by Lourdes Ibáñez, MD, PhD, professor of pediatrics and director of the fellowship program in pediatric endocrinology, University of Barcelona, Spain.

In a randomized trial of 36 adolescent girls who were not sexually active who had polycystic ovary syndrome — characterized by hirsutism and oligomenorrhea — a three-drug combination of low-dose spironolactone, pioglitazone, and metformin (SPIOMET) improved ovulation rates more effectively than did the standard oral contraceptive ethinylestradiol-levonorgestrel treatment.

The girls taking SPIOMET had greater normalization of hepatic and visceral fat, insulin, and markers of cardiovascular health, and after treatment, these values remained closer to normal in the girls who took SPIOMET than in those on oral contraceptives.


"In adolescent girls with PCOS, normalizing the amount of abdominal visceral and liver fat restores ovulation, besides normalizing the symptoms of androgen excess. These findings corroborate the notion that PCOS is not an ovarian disease but rather a pseudo–ovarian central obesity sequence," Dr Ibáñez told Medscape Medical News.

Clinically, "refocusing PCOS treatment toward early reduction of ectopic fat may prevent part of subsequent oligo-anovulatory subfertility," she said during her presentation.

Asked to comment, session moderator Stephen Franks, MD, FMedSci, professor of reproductive endocrinology at Imperial College Faculty Of Medicine, University of London, United Kingdom, told Medscape Medical News that "the idea of a cocktail is a good one," and "the idea of being able to intervene early metabolically makes absolute sense."

However, he also said, "How best to do that we won't know until we have larger and more diverse studies. [The Barcelona group has] unique data. That particular cocktail of drugs they use is an unusual one, and as far as I'm aware, nobody has replicated those findings. That's not to say there's anything wrong with them, it's just they haven't been replicated elsewhere."

Early Intervention Improves Ovulation, Reduces CV Risk Factors
In the open-label, single-center study, the 36 girls (mean age, 16 years) were randomized to either SPIOMET (50-mg/day spironolactone, 7.5-mg/day pioglitazone, and 850-mg/day metformin) or to the oral contraceptive pill ethinylestradiol plus levonorgestrel given 21/28 days.

The girls received the study drug for 12 months, and then were followed for another 12 months off treatment without any intervention. After two dropouts, 34 girls completed the study.

The primary end point was posttreatment ovulation rate, inferred from menstrual diaries and salivary progesterone. Secondary outcomes included body composition, abdominal fat, insulinemia, and androgenemia.

Posttreatment, the SPIOMET group had a 2.5-fold higher ovulation rate and a sixfold higher prevalence of normal ovulation compared with those girls in the oral-contraceptive group (both P < .001). Oligo-anovulation risk after SPIOMET was 65% lower than after the contraceptive pill.

There were no effects of either treatment on body weight, body mass index, lean mass, or subcutaneous fat.

SPIOMET also produced greater reductions in insulin production, C-reactive protein, and high-molecular-weight adiponectin and normalized visceral and hepatic fat to a greater degree.

And in the 24 months posttreatment, "Interestingly, the more loss of hepatic fat on treatment was followed by more ovulations," Dr Ibáñez commented.

Both treatments reduced androgen excess. The oral contraceptives did so faster and to a greater degree than did SPIOMET during treatment. However, posttreatment there was also a faster and more marked rebound of free testosterone in the oral-contraceptive group. And "the less the rebound posttreatment, the more ovulations," she noted.

For the future, she told Medscape Medical News, "Understanding the interactions between the components of this combination and other factors — ie, epigenetic factors — may uncover why [SPIOMET] has sustained benefits after discontinuation."

Dr Franks commented, "They've shown in their own cohort that this particular cocktail works best in terms of metabolic function, but it does need to be applied elsewhere."



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