Review

Department of Gynecological Endocrinology and Reproductive Medicine, Medical University of Innsbruck, 6020 Innsbruck, Austria

* Correspondence: [email protected]; Tel.: +43-512-504-23276 † These authors contributed equally to this work.

Citation: Reiser, E.; Lanbach, J.; Böttcher, B.; Toth, B. Non-Hormonal Treatment Options for Regulation of Menstrual Cycle in Adolescents with PCOS. J. Clin. Med. 2023, 12, 67. https://doi.org/10.3390/ jcm12010067

Academic Editors: Johannes Ott and Marlene Hager

Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Abstract: Menstrual irregularities are one of the main clinical symptoms caused by polycystic ovary syndrome (PCOS). Pharmacological treatment options for non-fertility indications to restore menstrual frequency play an important role in the management of PCOS. Oral contraceptive pills are commonly prescribed for adolescents with menstrual irregularities, however, when contraindicated or poorly tolerated, further pharmacological therapy is required. This systematic literature research aims to provide an overview concerning the effects of non-hormonal pharmacological treatment options on menstrual irregularities in adolescents suffering from PCOS. A systematic literature search in PubMed, Cochrane, Embase, Bio-SISS and Web of Science was performed, including literature from January 1998 to September 2022, using specific keywords in order to find related studies. n = 265 studies were identified of which n = 164 were eligible for further evaluation. Only four placebo-controlled studies were identified, with diverging inclusion and exclusion criteria. Available data on specific non-hormonal off-label use medication primarily consisted of metformin, Glucagonlike peptide 1 receptor agonists, thiazolidinediones, anti-androgen agents (spironolactone, finasteride, flutamide) and supplements (chromium picolinate, myo-inositol). However, only a few have partly pointed out beneficial effects on improving menstrual frequency in patients diagnosed with PCOS. In summary, metformin in dosages of 1500–2550 g/day, GLP-1—analogues and supplements were effective in regulation of menstrual cycles in adolescents diagnosed with PCOS. Menstrual frequency in adolescents with PCOS is essential to prevent hypoestrogenism with long-term consequences. In this context, MET is the most effective and cost- efficient in overweight adolescent girls, also showing beneficial effects in the regulation of insulin sensitivity, especially if COCs are contraindicated or not well-tolerated. Further studies are needed to evaluate therapies in lean and normal-weight girls with PCOS.

Keywords: polycystic ovary syndrome; oligomenorrhea; menstruation; metformin; GLP-1; menstrual cycle

Polycystic ovary syndrome (PCOS) affects approximately 6 to 13% of adolescent girls [1,2]. Diagnosis and treatment remain a challenge due to the considerable heterogeneity in its manifestation and complexity of this health condition in adolescent young women [3,4]. Key features for diagnosing PCOS in adolescents include irregular menstruation and hyperandrogenism, in addition to specific diagnostic criteria for menstrual cycle irregularities since menarche was established [5]. The presence of polycystic ovary morphology by transvaginal ultrasound can also occur in adolescents not suffering from PCOS and is not specific [4,5].

Adolescents with PCOS mainly seek medical advice to alleviate burdensome PCOSrelated clinical manifestations, such as acne, hirsutism, alopecia and oligo-/amenorrhea. To date, no pharmacological therapy has been approved by the FDA/EMA to treat clinical manifestations in adolescents suffering from PCOS [6]. According to a review by

J. Clin. Med. 2023, 12, 67. https://doi.org/10.3390/jcm12010067 https://www.mdpi.com/journal/jcm

Vitek et al. [7], the current state of knowledge indicates that data obtained in several studies on a host of pharmacological substances suggest potential beneficial effects in terms of symptom relief.

According to the international evidence-based guideline for the assessment and management of PCOS published in 2018, therapeutic pharmacological options for non-infertility indications include combined oral contraceptive pills (COC), metformin (MET), anti-obesity agents, anti-androgen agents and Inositol, addressing different clinical manifestations [5]. Formerly, routine treatment focused on oral contraceptive pills. Within the last 20 years, treatment of adolescents with PCOS mainly focused on COC. Recently, adolescents in general tend to prefer non-hormonal contraceptive options to hormonal contraceptives [8].

This review focusses on non-hormonal treatment options for menstrual irregularities in adolescents with PCOS including MET, Glucagon-like peptide 1 receptor agonists, thiazolidinediones (rosiglitazone, pioglitazone), anti-androgen agents (spironolactone, finasteride, flutamide), combination treatment with SPIOMET and supplements (chromium picolinate, myo-inositol).

The PubMed, Cochrane, Embase, Bio-SISS, and Web of Science databases, including studies, were searched from January 1998 to September 2022 by following the “preferred reporting items for systematic reviews and meta-analysis” (PRISMA). The following key words were used: oligomenorrhoea, adolescent, adolescence, PCOS, menstrual cycle, menstrual cyclicity, metformin, thiazolidinediones, spironolactone, flutamide glucagon-like peptide 1 receptor agonists, myo-inositol, herbal medicines. No abstracts or conference proceedings were included. Duplicates were removed and the remaining studies were screened by two independent authors. Selection process is displayed in Figure 1 (Flowchart). Information about yearly treatment costs were extracted from the Austria Codex, containing up-to-date professional information on all human and veterinary medicinal specialties approved in Austria. Some of the medication is covered by Austrian insurance, but since cost coverage differs between countries, the end user costs are listed.

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Figure 1. Flow diagram of the identification of studies via databases and registers.

An overview of the analyzed studies and the therapeutic effects of Metformin, GLP-1agonists, insulin sensitizers, anti-androgens, Myo-Inositol and supplements on menstrual irregularities in adolescents are presented in Table 1. An overview of treatment options, mode of action, indication, dose, side effects, safety during pregnancy, contraindications, and costs is demonstrated in Table 2.

Table 1. Included Literature. (Abbreviations are explained below).

Sample Size (Trial/ Control Group)

Length (Months (mo) or Weeks (we))

Outcome (Menstrual Cyclicity)

Author, Year

PCOS Criteria Age (Years) BMI (kg/m2) Intervention

Other Outcomes

MET 1000 mg/d COC: 30 µg EE and norgestiate 0.25 mg

clinical/biochemical hyperandrogenism and oligomenorrhoea

40.1 ± 2.1 (COC) 37.3 ± 1.3 (MET)

Regular menstrual cycle in both groups

Weight/BMI ↓ * Acne score ↓ * Testosterone ↓ * Hirsutism ↓ *

Allen, 2005 [9]

12–21

16/15 6 mo

MET 1700 mg/d COC: 30 µg EE and 15 mg progestin Placebo

Regular menstrual cycle in MET/COC group

Weight/BMI (only MET group) ↓ * Hirsutism ↓ *

El Maghraby, 2015 [10]

Rotterdam criteria

17.2 ± 2.0 -

40/40/39 24 mo

Regular menstrual cycle

Weight/BMI ↓ Androgen levels ↓ Hirsutism ↓ *

De Leo, 2006 [11]

Rotterdam criteria

MET 1700 mg/d

15–18 25.5–27.0

18 12 mo

Menstrual irregularity (<eight menses in the preceding year) and clinical or biochemical evidence of hyperandrogenism

MET 1700 mg/d COC: 30 µg EE and desogestrel 0.15 mg lifestyle modification placebo

Regular menstrual cycle in COC group/no difference in other groups MET group 75% of cycles with ovulation

Hoeger, 2008 [12]

Weight/ BMI ↓ *

12–18 34.3–37.8

16/21/21/19 8 mo

Oligo/amenorrhoea + clinical or biochemical evidence of hyperandrogenism

91% regular menstrual cycle during MET

Glueck, 2001 [13]

MET 1500–2550 g/d

14–18.9 33.6

11 9 mo

Weight ↓

Weight ↓ * Cholesterol ↓ * Triglyceride ↓ * HOMA↓ * Testosterone↓ *

74% with regular menstrual cycle

MET 1500–2550 g/d + diet

Glueck, 2006 [14]

Rotterdam criteria

<20 30.8

35 12 mo

Weight/BMI ↓ * Testosterone ↓ * Cholesterol ↓ * Triglyceride ↓ * HOMA↓ *

82% with regular menstrual cycle

MET 1500–2550 g/d + diet

Glueck, 2009 [15]

Rotterdam criteria

14–17 30.4

20 12 mo

MET 2000 mg/d COC: 30 µg EE and 1 mg norethindrone acetate

Androgen (only COC group) ↓ * BMI/ weight ↓ * HOMA ↓

Number of cycles higher in COC group

Al-Zubeidi

10/12 6 mo

and Klein, 2014 [16]

NIH criteria 14–18 33.7

MET

Ladson, 2010 [17]

NIH/NICHD criteria

16.1 ± 1.5 35.9–37.1

2000 mg/d ± lifestyle

22 6 mo No difference Acne score ↓ *

modification

Hirsutism and/or biochemical hyperandrogenemia, and oligoamenorrhea + precocious pubarche

Regular menstrual in

all patients, irregular within 3 months after withdrawal

Hirsutism ↓ * Testosterone levels ↓ *

Ibáñez, 2000 [18]

MET 1275 mg/d

13–20 21.9 ± 0.9

8 6 mo

Alpha-Lipoic Acid (ALA) 400 mg and MYO 1000 mg/2×/d placebo

Improved menstrual frequency

Cirillo, 2019 [19]

Rotterdam criteria

hirsutism ↔ acne ↔

17.2 ± 0.7 -

23/21 3 mo

Clinical features of PCOS (Chronically anovulating, oligo/amenorrhea, hyperandrogenism)

Improved menstrual frequency (91% with regular cycles at the end of therapy)

Body weight/BMI ↔ Insulin resistance ↓ *

Narsing, 2009 [20]

Pioglitazone 30 mg/d

15–25 29.5 ± 7.9

22 6 mo

Body weight ↑ * Hirsutism and acne ↓ * Insulin resistance ↓ *

Improved menstrual frequency

Stabile, 2014 [21]

Rotterdam criteria

Pioglitazone 30 mg/d

19.4 ± 3.8 25.2 ± 5.1

15/15 6 mo

Body weight/BMI ↔ glucose tolerance status ↔ visceral adiposity ↓ * (With rosiglitazone)

COC: 30 µg EE and drospirenone

No changes in menstrual cyclicity

Tfayli, 2011 [22]

NIH criteria 10–20 35.6 ± 1.5

23/23 6 mo

1. 3 mg ROS
2. 4 mg/d

Clinical diagnosis of PCOS based on hyperandrogenism, chronic anovulation, polycystic ovaries by ultrasound

Hirsutism ↓ * Androgen levels↓ * Ovulatory cycles ↑ * Ovarian volume ↓ *

Improved menstrual frequency

De Leo, 1998 [23]

Flutamide 500 mg/d

16–19 -

8 6 mo

Clinical features of PCOS (oligo-

No changes in menstrual cyclicity

Ibáñez, 2000 [24]

Flutamide 250 mg/d

Hirsutism ↓ * BMI ↔

16.8 ± 0.3 -

18 18 mo

/amenorrhea, hyperandrogenism)

Hirsutism ↓ * Serum Testosteron Levels ↓ *

26.8 ± 4.0 (SPIRO) 26.5 ± 5.6 (MET)

MET 1000 mg/d SPIRO 50 mg/d

Improved menstrual frequency

Ganie, 2004 [25]

35/34 6 mo

NIH criteria 22.6 ± 5.0

Clinical diagnosis of PCOS based on hirsutism (score > 8 on modified FerrimanGallwey scale) and oligomenorrhea (menstrual intervals

COC: 20 µg EE and 100 mg levonorgestrel SPIOMET: spironolactone 50 mg/d, pioglitazone 7.5 mg/d and metformin 850 mg/d

Improved menstrual frequency (with SPIOMET even in the follow-up year)

Ovulation rates ↑ * (with SPIOMET) Hepatic-visceralfat-excess ↓ * (with SPIOMET) HOMA-IR ↓ * (with SPIOMET)

12 mo of treatment and 12 mo follow-up without treatment

15.9 ± 0.2 (EE and Levonorgestrel) 15.7 ± 0.2 (SPIOMET)

24.9 ± 0.8 (EE and Levonorgestrel) 24.2 ± 0.7 (SPIOMET)

Ibáñez, 2020 [26]

31/31

>45 days)

Acne and hirsutism ↔ Free testosterone levels ↓ *

Chromium (III) picolinate 1000 µg/d

Improved menstrual frequency

Amr, 2005 [27]

Rotterdam criteria

BMI SDS 1.9 ± 0.7

14–17

35 6 mo

* = statistically significant, ↓ = reduction., ↔ = stable, ↑ = increase.

Table 2. Overview of treatment options, mode of action, indication, dose, side effects, safety during pregnancy, contraindications, and costs. (Abbreviations are explained below).

Teratogenic Effects (FDA Pregnancy Category)

Off-Label Reproductive Use

Treatment Costs (per Year)

Mechanism(s) of Action

Main Side Effects

Medication

Dosage

Contraindications

Safety during Pregnancy

Treatment Mode of Action Indication Dose Side Effects

Contraindications Costs

Enhancement of insulin sensitivity Inhibition of hepatic glucose production Increased glucose uptake in the muscle Hyperandrogenemia ↓

Improvement of

ovulation rates, menstrual regulation, hirsutism,

Nausea/vomiting/ abdominal pain/ diarrhea

Severe liver/kidney/heart insufficiency

850– 2550 mg/d

Pregnancy category B

58.4 Euro (1500 mg/d)

Metformin [28]

weight loss

Increased MYO levels improve D-chiro-inositol/MYO ratio and reduce androgen production

Myo-Inositol [29,30]

Nutritional supplement

No data available

197.1 Euro (2000 mg/d)

2000 mg/d No Unknown

Insulinotropic effects: hepatic glucagon release ↓, delays gastric emptying, intestinal motility ↓, glycemic control ↑, stimulates the hypothalamic satiety center, appetite↓, weight loss

History of medullary thyroid carcinoma/ MEN 2/pancreatitis/renal impairment

Glucagon-like peptide receptor agonists: exenatide, liraglutide [31,32]

LIRA 25,301.8 Euro (3 mg/d) Exenatide 91,417.9 Euro (20 µg/d)

Nausea/vomiting/ abdominal pain/ diarrhea/injection site reaction/ headache

Liraglutide: 1.2–3 mg/d

Weight loss, menstrual regulation

Pregnancy category C

Exenatide: 20 µg/d

PPAR-g receptor agonist: enhances cellular responsiveness to insulin, insulin-dependent glucose disposal ↑, glycaemic control ↑

Weight gain/ abnormal vision, respiratory infection,

Heart failure/liver failure/bladder cancer (pioglitazone)

Improvement of

Pioglitazone: 30 mg/d rosiglitazone: 4–8 mg/d

Thiazolidinediones:

Pioglitazone 164.25 Euro (30 mg/d)

ovulation rates, menstrual regulation

Pregnancy category C

rosiglitazone, pioglitazone [33]

numbness

Competitively binds androgen receptors → inhibits androgen uptake and/or nuclear binding of androgen

Breast swelling or tenderness/nausea/

Treatment of signs of hyperandrogenism (e.g., acne, hirsutism)

Liver and kidney problems/ heart disease

Pregnancy category D

262,8 Euro (250 mg/d)

Flutamide [34]

<250 mg/d

vomiting/abnormal liver function

Reduced libido/ depression/ headaches/ gastrointestinal disorders

Treatment of signs of hyperandrogenism (hirsutism)

Inhibitor of 5-alpha reductase → antiandrogenic effects

Pregnancy category X

Pregnancy/ liver disease/

153.3 Euro (5 mg/d)

Finasteride [35]

2.5–5 mg/d

Gastrointestinal problems/ headache/ tenderness of the breasts/ menstrual disorders/dizziness

Treatment of signs of hyperandrogenism (e.g., acne, hirsutism)

Hyperkalemia/ chronic adrenal insufficiency

Aldosterone antagonist, diuretic with antiandrogen properties

315.35 Euro (50 mg/d)

Pregnancy category C

Spironolactone [25]

50 mg/d

The exact mechanism of action is not known → improved insulin sensitivity

Menstrual regulation and ovulation rates

200– 1000 µg/d

No data available

No data available

Chromium (III) picolinate [36]

Unknown

30 Euro

↑ = increase, ↓ = decrease and → = leading to.

1. 3.1. Metformin
2. 3.2. Glucagon-like Peptide 1 Receptor Agonists

Glucagon-like peptide 1 receptor agonists (GLP-1RA) share similar glucoregulatory and central characteristics of the endogenous gut hormone GLP-1, a member of incretin hormones secreted in the intestinal tract in order to enhance postprandial insulin secretion [31]. Due to these insulinotropic effects, GLP-1 reduces hepatic glucagon release, delays gastric emptying, slows down intestinal motility, improves glycemic control, stimulates the hypothalamic satiety center and induces weight loss as a result of suppressing appetite [32].

The clinical effectiveness of GLP-1RA with regard to the treatment of DM2 and weight management in people suffering from obesity (BMI >30 kg/m2 or >27 kg/m2 with at least one weight-related coexisting condition, such as dysglycemia, hypertension, dyslipidemia

or obstructive sleep apnea) led to their approval by the FDA and EMA for the indications mentioned above [37,38].

Owing to the fact that PCOS is often associated with impaired glucose tolerance and higher rates of obesity, GLP-1RA, Liraglutide (LIRA, a long-acting GLP-1RA) and Exenatide (EX, a short-acting GLP-1RA) in particular, have recently been considered to be a prospective therapeutic option for the management of women with PCOS and obesity [39].

To our knowledge, no clinical trials are currently available which assess the effects of GLP-1RA on menstrual regularity in obese adolescents with PCOS.

Ornstein et al. (2011) found that there is evidence that weight loss achieved through diet management and lifestyle intervention can help restore menstrual regularity in obese adolescents with PCOS (12–22 years) [40].

Due to the lack of studies assessing the effects of GLP-1RA in adolescents with PCOS on menstrual irregularities and the great heterogeneity concerning dosage, the length of treatment and outcome in adult women, studies are required to determine benefits and safety issues before the treatment with GLP-1RA can be advised. Common side effects of GLP-1RA reported in the vast majority of trials were gastrointestinal in nature. Another important aspect which has to be taken into consideration are the high treatment costs of LIRA and EX, amounting to a considerable sum of €25,301.8 with LIRA and €91,417.9 with EX per year.

1. 3.3. Thiazolidinediones: Rosiglitazone and Pioglitazone
2. 3.4. Antiandrogens Flutamide, Finasteride, Spironolactone and SPIOMET

Elevated androgen levels which clinically manifest as hirsutism, acne and/or alopecia are often associated with high levels of suffering among adolescents with PCOS. For that reason, antiandrogen agents have been considered an essential therapeutic strategy to lower androgen excess and thus attenuate their clinical manifestations. Two types of antiandrogens have been proposed for the management of PCOS: antagonists to the androgen receptor, such as spironolactone and flutamide and inhibitors of 5-alpha reductase, such as finasteride [42]. However, there is limited data on the clinical effects of treatment with antiandrogens and combined therapy in adolescents with PCOS.

1. 3.5. Flutamide
2. 3.6. Finasteride
3. 3.7. Spironolactone
4. 3.8. SPIOMET

Ibáñez et al. [26] analyzed two open-label controlled randomized pilot studies in which they compared treatment with a COC (20 µg EE, 100 mg levonorgestrel) with a low-dose combination (SPIOMET) of SPIRO (50 mg/d), pioglitazone (7.5 mg/day) and MET (850 mg/d) for 1 year in 62 non-obese and non-diabetic adolescent girls (mean age 15.8 years) with PCOS. In the post-treatment year menstrual cycles remained more regular in 90% of the adolescents treated with SPIOMET and 42% of adolescents treated with OC.

The costs of treatment with spironolactone and flutamide amount to €315.4 and €262.8 per year, respectively.

Due to lack of data and high-quality RCTs with sufficient sample sizes investigating the effects of antiandrogens on regulation of menstrual cycles, further studies are needed before treatment options with antiandrogens in adolescents with PCOS can be recommended.

1. 3.9. Supplements
2. 3.10. Myo-Inositol

Myo-inositol (MYO) belongs to the vitamin B complex group. In women with PCOS, reduced MYO levels are associated with insulin resistance [47]. In PCOS patients with hyperinsulinemia the D-chiro-inositol (DCI)/MYO is increased (by a reduction of MYO), leading to an overproduction of androgens in the ovary [48–50]. MYO administration can lead to the following improvements: regular menstrual cycles, ovulation, reduced testosterone levels, and reduced insulin resistance in adult women with PCOS [29,30].

Only one study reported on the influence of MYO on menstrual cyclicity in adolescent girls with PCOS:

In the study by Cirillo et al. [19], 23 adolescent PCOS patients (mean age: 17.22 ± 0.72) assigned to treatment with an association of 400 mg Alpha-Lipoic Acid (ALA) and 1000 mg MYO (2×/d) for 3 months and once daily for further 3 months were compared to 21 matched healthy controls. Menstrual frequency was improved in the PCOS patients as follows: Five oligomenorrheic patients presented regular cycles, and four amenorrhoeic adolescents developed oligomenorrhoea.

MYO is currently considered an experimental therapy in PCOS by the ESHRE guideline [5]. Yearly costs are 197.10 Euro for the treatment with 1000 mg/day.

Given the fact that PCOS is a lifelong condition patients have to cope with, pharmacological treatment options targeting specific clinical manifestations of PCOS are required. Menstrual disorders, oligo- and amenorrhea in particular, are one of the main clinical manifestations in PCOS, primarily treated with COCs. However, not all patients benefit from COCs due to side effects and adverse reactions caused by hormonal therapy. In order to increase the number of therapy options in adolescents suffering from PCOS, the effects on menstrual frequency of various off-label use medications approved for other indications have been investigated. There is evidence that enhancing insulin sensitivity is associated with improved menstrual frequency, which suggests that medication targeting glucose metabolism and weight control exerts beneficial effects on regulation of the menstrual cycle, especially in overweight women [51]. Metformin shows an overall benefit, while GLP-1RA

and ROS show conflicting data on improvement of menstrual frequency or were only studied in adult women. The meta-analysis by Al Khalifah et al. [42] showed no statistically important difference among the interventions (metformin, oral contraceptives, placebo, pioglitazone, spironolactone, flutamide, and lifestyle interventions) in improvement of menstrual cycles in adult women.

Several studies investigating the effect of non-hormonal treatment of women with PCOS are currently conducted as displayed at clinicaltrials.gov as of 13 December 2022 (Metformin: 178, Myo-Inositol 43, Glucagon-like peptide receptor agonists: 20, Thiazolidinediones: 3, Spironolactone: 11, Flutamide: 6, Chromium picolinate: 2, cinnamon: 4). However, only 11 studies focus on adolescent PCOS patients. This low number can certainly be explained by the stricter requirements and difficult feasibility of studies in minors. Nevertheless, the increasing number of overweight adolescents at risk under COC strengthen the justification of conducting clinical trials in this cohort [42]. Especially therapeutic options with GLP-1-agonists in adolescents with PCOS seem promising. Due to the lack of studies in adolescents with PCOS, results of studies in adult women could be considered to evaluate new options for girls:

An improvement of menstrual irregularities by the GLP-1- agonist liraglutid was found in several studies: Liraglutid treatment resulted in a significantly higher frequency of menstrual bleedings compared to placebo with no change in the frequency of menstrual bleeding [52]. Similar results were found in a 26-week placebo-controlled trial: 72 overweight women with PCOS were assigned to receive either liraglutid or placebo in a 2:1 ratio. Significant results were achieved in the liraglutid group with regard to menstrual frequency [53]. On the other hand, in the following studies no superiority of either metformin or liraglutid was found: No statistically significant results were reached when analyzing changes in menstrual patterns in obese women with PCOS in any of the three treatment arms metformin, liraglutid or the combination of both over 12 weeks [54]. Assumingly, the duration of treatment was too short to notice significant effects. Another study, also conducted over 12 weeks, showed similar results as no significant changes in menstrual frequency between metformin and liraglutide treatment were found [55].

Further long-term studies with GLP-1-agonists are needed to evaluate the impact on PCOS symptoms. Possibly, promising results might open new prospects of assumption of cost by health insurances as at the moment GLP-1-agonists are only paid by the insurance in case of metformin resistance in DM Typ2 patients.

Treatment of hyperandrogenism with antiandrogen medication is mainly recommended to ameliorate clinical manifestations of androgen excess (e.g., hirsutism and acne). The combination of metformin and spironolactone showed superior effects on menstrual frequency compared to monotherapy with either metformin or spironolactone over six months [56]. However, the role of antiandrogen agents to improve menstrual frequency remains controversial [5]. Importantly, in order to avoid possible feminizing effects on genital development of male fetuses, effective contraception should be part of the counselling and be prescribed along with antiandrogenic medication whenever treating sexually active adolescents [6]. Early initiation of antiandrogen treatment in adolescents may even have an impact on the incidence of childbirth after spontaneous conception in adulthood. The period of time to first childbirth after spontaneous conception was reduced in women who received antiandrogenic medication earlier during adolescence compared to women who were treated with antiandrogenic medication after adolescence [57].

An important treatment option, which has not been discussed so far, as no data for adolescents exist, consists of phytotherapeutic extracts of the Vitex agnus-castus L. fruit. It is commonly prescribed to alleviate a range of gynecological disorders, such as premenstrual syndrome (PMS), abnormal uterine bleeding, hyperprolactinemia, luteal phase defect and premenstrual mastodynia [58]. A randomized triple-blind placebo-controlled clinical trial compared treatment with low-dose COC, Vitex agnus-castus L. and the impact on regularization of menstrual cyclicity for three months in women with PCOS. Treatment with Vitex agnus-castus L. showed similar beneficial effects on regulating menstrual

frequency compared to low-dose oral contraceptives [59]. As Vitex agnus-castus L. is welltolerated, research of the effects in adolescent girls and the approval for this age group could be promising.

Combined therapy options addressing various manifestations have shown promising results in symptom management in PCOS patients, but data are still limited. The additives of combined therapies vary widely, therefore conclusions are difficult to draw.

Data on additional supportive therapy options including herbal medicines and supplements suggest a benefit on regulation of the menstrual cycle. Unfortunately, no placebocontrolled trials in adolescents were published so far. In adult women with PCOS, a review of 33 studies with herbal medicines showed beneficial effects on menstrual cycles and hyperandrogenism in women with PCOS but especially pre-clinical studies to explain the effects of herbal medicines are needed [60].

This is the first review solely focusing on non-hormonal treatment of menstrual irregularities in adolescent PCOS patients. The exclusion of a rather large number of studies due to a lack of data in adolescents can be considered as a possible limitation. Criteria for PCOS in adolescents have only been defined in 2017/2018, so all studies before that date use inconsistent definitions which complicates the comparison of studies. Furthermore, studies with adolescents may include very limited numbers of participants. The fact that a large number of girls decide on hormonal contraceptives hinders the evaluation of nonhormonal treatment options.

One main aspect remains cost-benefit efficacy as it has to be taken into consideration when prescribing medical agents. Yearly treatment costs of several ten thousands of Euro in case of GLP-1RA have to be compared to 58 Euro for MET or similar costs for COC.

Effectiveness and safety issues were not fully evaluated in adolescents, highlighting the need for further high-quality research on pharmacological treatment in adolescents suffering from PCOS.

Adolescents with PCOS mainly seek their gynecologist due to menstrual irregularities. Oligo- and Amenorrhea lead to hypoestrogenism with long- term consequences. MET seems to be an effective treatment option in overweight adolescent girls with PCOS. Supplements, such as MYO and Chromium (III) picolinate, and anti- androgens, such as spironolactone, also in combination with MET and piogliatazone, might be efficient alternatives. Further studies are needed to evaluate treatment options especially in lean and normal-weight adolescent girls with PCOS.

Author Contributions: Conceptualization: B.B. and B.T.; methodology: J.L., E.R., B.B. and B.T.; data analysis: J.L. and E.R.; drafting of the manuscript: J.L., E.R. and B.B.; critical revision of the manuscript for important content and approval of the final version: all authors. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest.