Toward a Treatment Normalizing Ovulation Rate in Adolescent Girls With Polycystic Ovary Syndrome

Lourdes Ibáñez; Marta Díaz; Cristina García-Beltrán; Rita Malpique; Edurne Garde; Abel López-Bermejo; Francis de Zegher


J Endo Soc. 2020;4(5) 

In This Article

Abstract and Introduction


Adolescent polycystic ovary syndrome (PCOS) is characterized by androgen excess and oligomenorrhea, and commonly driven by hepato-visceral fat excess ("central obesity") ensuing from a mismatch between prenatal and postnatal nutrition, on a background of genetic susceptibility. There is no approved treatment for adolescent PCOS.

We report the pooled results of 2 pilot studies in nonobese girls with PCOS (N = 62, age 15.8 years) that compared the effects of randomized treatment for 1 year, either with an oral estro-progestogen contraceptive (OC), or with a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET, targeting the excess of ectopic fat).

Auxological and endocrine-metabolic variables (including fasting insulin, androgens, high-molecular-weight adiponectin [HMW-adiponectin], and microRNA [miR]-451a), body composition (dual x-ray absorptiometry) and hepato-visceral fat (magnetic resonance imaging) were assessed on- and posttreatment. Data from menstrual diaries were combined with weekly salivary progesterone measurements to infer ovulation rates during the second and fourth quarter of the posttreatment year.

OC and SPIOMET treatment reduced the androgen excess comparably, and had no differential effects on total-body lean or fat mass. However, SPIOMET was accompanied by more broadly normalizing effects, including on hepato-visceral fat and on circulating insulin, HMW-adiponectin, and miR-451a. On average, there were 3-fold more ovulations post-SPIOMET than post-OC; normovulation was only observed after SPIOMET; anovulation was >10-fold more prevalent post-OC.

Pooled results of randomized studies in nonobese adolescent girls with PCOS indicate that SPIOMET treatment leads to an overall healthier, more insulin-sensitive condition—with less ectopic fat—than OC treatment, and to a more normal posttreatment ovulation rate.


There is no approved treatment for polycystic ovary syndrome (PCOS), a prevalent condition in adolescent girls and young women.[1,2] Many of these patients are guided into a trajectory that starts with oral contraceptive (OC) treatment, leads into oligo-anovulatory subfertility, then into the use of assisted reproductive techniques, and ultimately into pregnancies with a double-to-triple risk for complications (such as gestational diabetes, preeclampsia, and preterm birth) potentially with lifelong sequelae in the offspring.[2]

Evidence is converging toward the insight that adolescent PCOS is frequently driven by hepato-visceral fat excess ("central obesity") ensuing from a mismatch between (rather restrictive) prenatal and (rather abundant) postnatal nutrition, on a background of (epi)genetic susceptibility.[3–5] This insight has prompted the exploration of an alternative treatment for PCOS consisting of the intake of a low-dose combination of spironolactone (a mixed anti-androgen and anti-mineralocorticoid, also activating brown adipose tissue).[6] with pioglitazone and metformin (2 insulin sensitizers acting through different mechanisms) (SPIOMET) for 1 year. This combination proved to have more normalizing effects than OC treatment, in particular, on ectopic fat excess, insulin sensitivity, and posttreatment ovulation rate.[7] The limited power of the first study (N = 34) prompted the launch of a second study with virtually identical design. Here we report the pooled results of both studies in nonobese girls with PCOS (N = 62).