A Clinical Trial to Evaluate the Efficacy, Tolerability, and Safety of a Fixed Dose Combination of Spironolactone, Pioglitazone & Metformin (SPIOMET) in Polycystic Ovary Syndrome (PCOS)

Inclusion Criteria:

1. Age range within the AYAs category (> 12.0 years and ≤ 23.9 years at study start) (96); Given that another inclusion criterium is gynaecological age (years elapsedsince menarche) of 2 years or more, and that menarche before age 10.0 years is anexclusion criterium (please see exclusion criteria below), the youngest participantwill be older than 12.0 years at study start (97). The upper age limit at study startis set at 23.9 years (thus, 24.9 years when the active treatment ends, see section 7.Conduct), in order to avoid early dropouts due to an increase in the prevalence ofpregnancy wish beyond that age in most European countries;
2. Gynaecological age of 2 years or more;
3. Clinical androgen excess, as defined by the presence of hirsutism (modifiedFerriman-Gallwey score ≥ 4) (17,98) and/or inflammatory acne (Leeds scale)unresponsive to medications (3,95,99). The scarce normative data existing inadolescents suggest that an adult level of hirsutism is reached around 2 years aftermenarche (100);
4. Biochemical androgen excess, as defined by increased total testosterone (≥50 ng/dL),and/or a FAI higher than 3.5 [FAI, total testosterone (nmol/L) x 100/SHBG (nmol/L)],in the follicular phase of the cycle (days 3-7) or after 2 months of amenorrhea (3,100,101); Measurements of total testosterone and/or FAI are the most recommendedassessments to screen for hyperandrogenaemia (3,19,95,102). Serum testosterone attainsadult levels shortly after menarche; thus, an elevation of serum testosteroneconcentrations and/or FAI above adult norms and assessed in reliable referencelaboratories constitutes biochemical evidence of hyperandrogenism (3,19,95,100). It isaccepted that this upper limit can be set at 45 ng/dL for testosterone and at 3.5 forFAI (3,95,100,101,102,103). Direct free testosterone assays, such as radiometric orenzyme-linked assays, preferably should not be used in the assessment of biochemicalhyperandrogenism, as they demonstrate poor sensitivity, accuracy and precision (17);
5. Menstrual irregularity, as defined by ≤ 8 menses per year corresponding to an averageinter-menstrual time of ≥45 days (3,95,100); Most adolescents establish a menstrualinterval of 20-45 days within the first 2 years after menarche (3,95). Three yearsafter menarche, the 95th percentile for cycle length is 43.6 days (104); thus, cycleslonger than 45 days (<8 periods/year) at or beyond this gynaecological age areconsidered abnormal and are evidence of oligo-anovulation;
6. Written informed consent obtained from the patient, or assent from the patient andconsent by the parents or the legally acceptable representative if she is a minor (fordetails, see section 7. Conduct, under informed consent).

Exclusion Criteria: