Notes on Oral and Vaginal Hormonal Contraceptives in Women with PCOS

Introduction

• Polycystic ovary syndrome (PCOS) is the most common endocrine disorder, affecting 5–18% of women of reproductive age. $[1,2]$

• Diagnosis of PCOS requires at least two of the following three criteria (Rotterdam criteria $[3]$ and international evidence-based PCOS guideline $[4]$):

  1. Polycystic ovaries on gynecological ultrasonography.

  2. Oligo- or anovulation.

  3. Clinical and/or biochemical hyperandrogenism (hirsutism or high serum testosterone or androgen levels).

• Women with PCOS have an increased risk for:

  • Glucose metabolism disorders $[5,6]$

  • Obesity

  • Hypertension

  • Dyslipidemia

  • Insulin resistance (IR)

  • Metabolic syndrome $[5–8]$

• Combined hormonal contraceptives (CHCs) are the first-line treatment for menstrual irregularity and hirsutism, common PCOS-related clinical manifestations. $[4,9]$

• CHCs can induce unfavorable metabolic effects, especially on glucose metabolism in the general population. $[10–13]$

• Recommendations for CHC use in women with PCOS are often based on studies of women without PCOS, with limited specific research on CHC use in PCOS.

• There is a possibility that CHCs may worsen existing metabolic disorders in women with PCOS. $[14]$

• Some studies suggest combined vaginal contraception (CVC) may cause fewer metabolic effects than combined oral contraception (COC) in women without PCOS, but findings are inconsistent. $[12,15]$

• International evidence-based PCOS guidelines recommend COCs for menstrual irregularity and hyperandrogenism but do not specify dosage, mode of administration, or specific preparation. $[4]$

• The Amsterdam ESHRE/ASRM consensus highlighted the need for head-to-head trials comparing different CHC strategies and longitudinal follow-up studies on CHC use in women with PCOS. $[3]$

• Objective: To compare the hormonal and metabolic effects of COC and CVC in women with PCOS after nine weeks in a randomized controlled trial.

Materials and Methods

• Randomized, prospective, open-label, single-centered study.

• Conducted at Oulu University Hospital, Finland, between 2011 and 2016.

• Approved by the Ethics Committee of Oulu University Hospital.

• All participants provided written consent.

• Registered at ClinicalTrials.gov (NCT01588873).

Study Population

• Participants were selected from the hospital register using the ICD10 diagnosis code for PCOS (E 28.2).

• Eligibility criteria:

  • Aged 18–40 years

  • Healthy, without medical contraindications for CHC use (e.g., high blood pressure, migraine with focal aura, thromboembolism risk factors, liver disease, unexplained vaginal bleeding, diagnosed or suspected cancer, or estrogen-dependent tumor)

  • Not using any medication

  • Non-smoker

  • Not pregnant or breastfeeding

  • No hormonal or cortisone medicines for at least 2 months prior to study entry.

• Participants were randomized (1:1) to:

  • Combined hormonal oral contraceptive pill (COC group): ethinylestradiol (EE) 20 µg and desogestrel 150 µg (Mercilon®; Organon Ltd., Dublin, Ireland).

  • Combined hormonal contraceptive vaginal ring (CVC group): EE 15 µg/day and etonogestrel (active metabolite of desogestrel) 120 µg/day (NuvaRing®; N.V.Organon, Oss, Netherlands) continuous for 9 weeks.

  • Randomization list was computer-generated.

• Two clinical examinations:

  • Baseline

  • After 9 weeks of treatment

    • Gynecological examination

    • Transvaginal ultrasound (endometrium thickness, ovarian volumes, and number of follicles)

    • Blood sampling for hormonal and metabolic parameters

    • Oral glucose tolerance test (OGTT)

• Baseline examination: between cycle days 1–3.

• Ninth week examination: within 3 days from the beginning of menstruation after contraceptive preparation discontinuation.

• 24 women with PCOS recruited: 13 in the COC group and 11 in the CVC group.

• Diagnosis of PCOS: according to the Rotterdam criteria.

Oral Glucose Tolerance Test

• 75 g 2 h oral OGTT performed after 12 h of fasting at baseline and 9 weeks.

• Blood samples: taken at 0, 30, 60, and 120 min.

• Calculations based on OGTT results:

  • Glucose and insulin areas under the curve (glucose AUC and insulin AUC)

  • Homeostatic model assessment of insulin resistance (HOMA-IR)

  • Homeostatic model assessment of β-cell function (HOMA-2β)

  • Matsuda index (whole-body insulin sensitivity) $[16]$

• These calculations were used to evaluate glucose tolerance, IR, and insulin sensitivity.

• Hyperinsulinemic-euglycemic glucose clamp: gold standard for evaluating insulin sensitivity but costly, time-consuming, invasive, and requires staff.

• Calculated indexes (HOMA-IR and Matsuda) estimate insulin resistance and sensitivity more easily. $[16–18]$

• HOMA-IR formula: $HOMA-IR = (insulin (mU/L) \times glucose (mmol/L) / 22.5)$

  • Quantifies IR from basal glucose and insulin levels.

  • Described in 1985 by Matthews et al. $[18]$

  • Strong linear correlation with the clamp. $[17,18]$

  • Used in various studies of PCOS to assess IR. $[19–22]$

• HOMA-2β formula: $HOMA-2β = (20 \times fasting insulin (µIU/mL) / fasting glucose (mmol/mL) - 3.5)$

  • Marker of basal insulin secretion by pancreatic β-cells. $[21]$

• Matsuda index formula: $Matsuda index = (10,000 / \sqrt{(fasting glucose \times fasting insulin) \times (mean glucose (OGTT) \times mean insulin (OGTT))})$

  • Estimates whole-body physiological insulin sensitivity. $[16]$

  • Correlates well with HOMA-IR and QUICKI in women with PCOS. $[23,24]$

Assays

• Serum samples for total testosterone (T) were analyzed using Agilent Triple Quadrupole 6410 liquid chromatography–mass spectrometry (LC-MS) with an electrospray ionization source in positive-ion mode (Agilent Technologies, Wilmington, DE, USA).

  • Multiple reaction monitoring: Used to quantify T using trideuterated T (d3-T).

  • m/z transitions: m/z 289.2 to 97 and 289.2 to 109 for T; 292.2 to 97 and 292.2 to 109 for d3-T.

  • Intra-assay coefficients of variation (CVs) for T: 5.3%, 1.6%, and 1.2% at 0.6, 6.6, and 27.7 nmol/L, respectively.

• Sex hormone binding globulin (SHBG): Analyzed by chemiluminometric immunoassays (Immulite 2000, Siemens Healthcare Diagnostics, Los Angeles, CA, USA) with a sensitivity of 0.02 nmol/L.

• Other assays using automatic chemical analyzers (Advia, 1800; Siemens Healthcare Diagnostics, Tarrytown, NY, USA):

  • Serum glucose

  • Total cholesterol

  • Low-density lipoprotein cholesterol (LDL-C)

  • High-density lipoprotein cholesterol (HDL-C)

  • Triglycerides

• Insulin: Analyzed using an automated chemiluminescence system (Advia Centaur; Siemens Healthcare Diagnostics, Tarrytown, NY, USA).

• High-sensitivity C-reactive protein (hs-CRP): Analyzed using immunonephelometry (BN ProSpec; Siemens Healthcare Diagnostics, Marburg, Germany).

• All samples (baseline and 9 weeks) from the same subject were analyzed in the same assay.

Statistical Analyses

• Power calculation: Based on a previous study comparing the metabolic effects of Mercilon® and Nuvaring® in young healthy women. $[13]$

  • The previous study showed a significant increase of 0.44 mmol in serum triglyceride levels at 9 weeks of treatment with both preparations.

  • The power analysis indicated that 17 women would be needed in each study group to reveal a similar increase in serum triglyceride levels.

  • Planned sample size: 40 women (20 in each group) to allow for dropouts.

  • Actual recruitment: 24 women (13 in the COC group and 11 in the CVC group) due to strong criticism in the media regarding thromboembolic risks linked to hormonal contraception.

• Variables: Presented as means with standard deviation (SD).

• Statistical tests:

  • Paired samples t-tests: For normally distributed variables to explore changes in hormonal and metabolic levels within the same study group at baseline and during the treatment.

  • Wilcoxon’s tests: For variables with a skewed distribution.

  • Linear mixed model (repeated measures) with a random intercept: To analyze the differences between the study groups and the change from baseline to the 9th study week.

    • Results were adjusted with the BMI and age of the participants.

• Statistical Package for the Social Sciences (SPSS) software (version 28.0 for Windows, SPSS Inc., Chicago, IL, USA) was used.

• Statistical significance level: $p ≤ 0.05$

Results

Anthropometric Parameters

• At baseline:

  • Women in the COC group were older (32.4 vs. 30.8 years, $p = 0.051$).

  • Their BMI tended to be higher (25.4 vs. 23.5, $p = 0.068$) compared to the CVC group.

• At baseline and 9 weeks of treatment:

  • No significant differences between the two study groups regarding:

    • BMI ($p = 0.245$)

    • Waist circumference (WC, $p = 0.812$)

    • Diastolic blood pressure (dBP, $p = 0.550$)

    • Systolic blood pressure (sBP, $p = 0.613$)

Serum Levels of Androgens and SHBG

• No significant differences in serum levels of testosterone at 9 weeks between the groups.

• SHBG levels:

  • Increased significantly in both groups between baseline and week 9 (COC p < 0.001, CVC p < 0.001).

• FAI:

  • Decreased in both groups (COC p < 0.001, CVC $p = 0.007$).

• Changes in SHBG and FAI between baseline and week 9 were similar within the groups.

Oral Glucose Tolerance Test (OGTT)

• Glucose levels at 60 min:

  • Higher after 9 weeks of treatment compared to baseline ($p = 0.008$, adjusted $p = 0.011$) in the CVC group.

• Glucose AUC:

  • Increased significantly in the CVC group ($p = 0.018$, adjusted $p = 0.034$).

• Fasting insulin levels:

  • Increased after 9 weeks of treatment in the COC group ($p = 0.037$, adjusted $p = 0.023$).

• Insulin levels at 120 min:

  • Increased in both groups (COC $p = 0.005$, adjusted $p = 0.004$; CVC $p = 0.028$, adjusted $p = 0.042$).

• HOMA-2β levels:

  • Increased significantly in the COC group ($p = 0.011$) but became non-significant after adjustments (adjusted $p = 0.10$).

  • Differed significantly between the two groups ($p = 0.037$, adjusted $p = 0.030$).

  • The increase in HOMA-2β levels was similar in both groups.

Serum Lipids and hs-CRP

• Triglyceride levels:

  • Increased significantly at 9 weeks of treatment in the CVC group (p < 0.001, adjusted p < 0.001).

  • Differences between baseline and 9 weeks ($p = 0.030$, adjusted $p = 0.103$); levels increased.

  • The change differed between the groups ($p = 0.542$, adjusted $p = 0.046$).

• hs-CRP levels:

  • Increased significantly after 9 weeks in the CVC group ($p = 0.032$, adjusted $p = 0.040$).

  • The levels differed between the groups after adjustments (adjusted $p = 0.021$).

  • The change in hs-CRP was similar in both groups ($p = 0.376$, adjusted 0.382).

Discussion

• Both COC and CVC decreased androgenicity but had only mild effects on glucose metabolism, IR, lipid profile, and chronic inflammation.

• CVC did not appear to have a more beneficial hormonal or metabolic profile than COC in PCOS, contrasting the initial hypothesis.

• CHC preparations are commonly used for PCOS to reduce menstrual abnormalities and hyperandrogenism.

• 20 µg EE + DSG (COC) or 15 µg/d EE/EGS (CVC) caused a 200–270% increase in SHBG levels and a 74–84% decrease in FAI levels, aligning with previous studies. $[13,15,25]$

• Some studies reported a greater increase in SHBG during oral CHC use. $[13,26]$

• Other studies have found that SHBG increased more during CVC treatment $[15,25]$ suggesting that routes are comparably efficient in improving hyperandrogenemia in PCOS.

• In some studies, CVC was considered to cause fewer adverse changes in glucose metabolism and insulin sensitivity in general female populations. $[15]$

• In this study, AUCglucose increased in the CVC group.

• A small compensatory increase in insulin secretion was observed in both groups, with fasting insulin and 120 min insulin levels increasing in the COC group and an increase in 120 min insulin levels in the CVC group.

• These results align partly with a previous study demonstrating a reduction in insulin sensitivity and an increase in AUCglucose levels among healthy young women given oral, vaginal, or transdermal CHCs. $[13]$

• Not all studies agree on the detrimental effect of CHCs on glucose metabolism.

• One study found no changes in carbohydrate metabolism in CVC users compared to COC users over five cycles. $[15]$

• CVC for 24 months was found to be safe in women with type 1 diabetes when estimated by glycosylated hemoglobin levels. $[27]$

• In the only randomized study performed with women with PCOS (n = 37), CVC improved insulin sensitivity and glucose tolerance, whereas COC (containing EE + drospirenone) worsened IR and insulin secretion at 6 months of treatment. $[28]$

• Comparisons with previous studies are challenging due to differences in CHC preparations and methods used to evaluate glucose metabolism and IR.

• The hyperinsulinemic-euglycemic glucose clamp technique is the gold standard for assessing IR and HOMA-IR, HOMA-2β, and the Matsuda index have been shown to be useful.

• These indexes have been shown to reliably reflect IR in several previous studies in women with PCOS. $[19–22]$

• It is unclear whether patients presenting mild IR display any additional clinical problems when compared to patients with a normal response to the clamp.

• There are also concerns that the evaluation of IR in women with PCOS is method-dependent, and there may be discrepancies between markers. $[29]$

• Lean women with PCOS may be more easily misclassified as insulin sensitive. $[30]$

• The results raise concerns that CVC may not be safer than COC in women with PCOS regarding its effects on glucose metabolism.

• Changes in lipid profile showed an increase in triglyceride levels in the CVC group, aligning with previous studies showing that COC use is associated with increased levels of triglycerides but also HDL and total cholesterol levels. $[14,31]$

• Oral EE administration has been shown to result in increased total cholesterol, mainly due to increased HDL cholesterol and triglycerides. $[32–34]$

• A similar effect during the use of CVC has also been described. $[35]$

• High triglyceride levels seem to be an independent predictor of the future risk of myocardial infarction $[36]$ and have been associated with elevated cardiovascular risks $[37]$, specifically in women $[37]$.

• A meta-analysis of CHC effects on the lipid profile in PCOS women concluded that desogestrel-containing CHCs increased triglyceride levels after 6 months of treatment. $[33]$

• A 9-week study is too short for solid conclusions regarding lipid profile changes with COC or CVC use, but the results do not support the recommendation that vaginal CHC be preferred to oral preparations to decrease the cardiovascular risks linked to PCOS.

• As an abnormal lipid profile is typically present in women with PCOS $[38]$, larger, long-lasting follow-up studies and real-world register data analyses are needed to clarify whether the use of CHCs (either oral or vaginal) will increase the risk of cardiovascular morbidity and mortality in women with PCOS.

• It is possible that the alleviation of hyperandrogenemia with CHCs overcomes mild impairments in metabolic parameters.

• Serum levels of hs-CRP increased in the CVC group after 9 weeks of treatment, with a similar hs-CRP change between groups.

• This result aligns with studies performed with oral and vaginal preparations $[39,40]$ and with recently published data showing EE to be a strong promoter of chronic low-grade inflammation. $[13,41]$

• This is an important finding, as women with PCOS have been shown to display chronic inflammation $[42,43]$, which, in turn, is associated with an increased risk of cardiovascular diseases and events, as well as overall mortality. $[44]$

• Estradiol valerate (EV) could display a more neutral effect on inflammation and lipids. $[41]$

• Further randomized studies are needed to clarify whether preparations containing EV instead of EE could be safer regarding cardiovascular risks in women with PCOS.

Strengths and Limitations

• Strengths:

  • PCOS diagnosis was made by a gynecologist.

  • Participants were homogeneous concerning ethnicity (all Caucasians).

  • Provides important data for future meta-analyses.

• Weaknesses:

  • The failure to recruit enough participants to meet the power calculation criteria for a sufficient sample size and to engage participants to finish the study.

  • A slightly higher BMI (non-significant) and age at baseline in the COC group may have influenced the results.

  • The power calculation was based on changes in triglycerides, not on glucose metabolism parameters or inflammation markers.

  • The hyperinsulinemic-euglycemic glucose clamp technique is the gold standard for IR measurement, but it is costly, time-consuming, invasive, and requires staff.

  • The short follow-up period does not permit conclusions to be drawn on the long-term consequences of the use of COC or CVC.

Conclusions

• CVC did not seem to be metabolically safer than COC in this short clinical study.

• There is a limited number of studies assessing different administration routes of CHCs for women with PCOS, and the results show some new data.

• Larger and longer studies are needed to compare the metabolic effects of CHC administration routes in PCOS.

Combined hormonal contraceptives (CHCs) like COC and CVC are commonly used for PCOS to reduce menstrual abnormalities and hyperandrogenism. They can decrease androgenicity. For example, 20 µg EE + DSG (COC) or 15 µg/d EE/EGS (CVC) caused a significant increase in SHBG levels and a substantial decrease in FAI levels, aligning with previous studies. However, it's important to note that CHCs may have only mild effects on glucose metabolism, insulin resistance, lipid profile, and chronic inflammation.