Letter to the Editor in response to: Microvascular endothelial function following the cessation of long‐term oral contraceptive pill use: A case report

We read the paper by Turner, Stanhewicz, Nielsen, Otis et al. (2023) with great interest, as it addresses an important gap in our understanding of long-term oral contraceptive pill use and the time course of changes in microvascular function post-cessation. The authors describe a case study of volitional cessation of long-term (12 years) oral contraceptive use, in which the 26to 29-year-old participant exhibited improved microvascular endothelial function (as indexed by the vasodilatory response to local heating and the nitric oxidecontribution component) compared with during oral contraceptive use. The authors surmise that vascular and endothelial function are impaired by oral contraceptive use, and thus understanding whether this proposed dysfunction can be recovered upon cessation has considerable implications for women’s health across the lifespan. The authors should also be applauded for several aspects of the study itself, including measurements at multiple time points during oral contraceptive use and throughout the menstrual cycle, which captures a more holistic picture of these exogenous and endogenous hormonal effects on the microvasculature. The data collected at 19–22 months post-cessation address an urgent yet long overlooked question that will be foundational in the design of further prospective experiments. We are writing to encourage this line of investigation and provide additional perspectives for future research. The augmented cutaneous vascular conductance (CVC) response to local heating (i.e., heating plateau %CVCmax) was the main basis for the conclusion that endothelial function was substantially increased after the cessation of long-term oral contraceptive use. However, the authors reported additional outcomes that are interesting to interpret alongside %CVCmax. Two of three maximal CVC measurements [raw values expressed as red blood cell flux per millimetre of mercury (RBC flux/mmHg)] during oral contraceptive pill use were greater than all post-cessation values. This mean difference in maximal CVC should not be disregarded and might instead be evidence of increased endothelium-independent vasodilatation with oral contraceptive pill use, while also explaining the resultant lower %CVCmax during the heating plateau. Indeed, this 19% mean reduction post-cessation aligns with the authors’ more recently published cross-sectional study

The augmented cutaneous vascular conductance (CVC) response to local heating (i.e., heating plateau %CVC max ) was the main basis for the conclusion that endothelial function was substantially increased after the cessation of long-term oral contraceptive use. However, the authors reported additional outcomes that are interesting to interpret alongside %CVC max . Two of three maximal CVC measurements   showing a mean ∼16% lower maximal CVC in naturally cycling non-users in the early follicular phase compared with combined oral contraceptive pill users in the placebo pill phase (not statistically significant, P = 0.10 in n = 9 per group; pills containing norethindrone, n = 4; norgestimate, n = 1; desogestrel, n = 1; drospirenone, n = 3). This also aligns with data from Limberg et al. (2016), who observed greater β-adrenergicand nitroprusside-mediated vascular conductance in women in the placebo phase of combined oral contraceptive use (norethindrone, n = 2; norgestimate, n = 3; desogestrel, n = 3; drospirenone, n = 1; unknown, n = 2) compared with non-users in the early follicular phase and proposed that the vascular smooth muscle is more responsive to nitric oxide in women using oral contraceptives.
The participant in this study was using a combined oral contraceptive containing drospirenone (0.02 mg ethinyl estradiol and 3.0 mg drospirenone), which Turner, Stanhewicz, Nielsen, Otis et al.
(2023) specify repeatedly throughout to add important context to their findings. Although this fourth-generation progestin has been associated with greater thromboembolic risk than other progestins, in vitro studies of drospirenone (Simoncini et al., 2007) and in vivo studies, whereby all (desogestrel or drospirenone; Thompson et al., 2011) or a considerable portion (∼40%; desogestrel or gestodene; John et al., 2000) of the women sampled were using pills containing third-and fourth-generation progestins, also collectively indicate that newer-generation progestins appear to enhance endothelial nitric oxide synthase expression and concurrently facilitate the beneficial effects of synthetic estradiol on endothelium-dependent vasodilatation. As would therefore be expected, the participant in the present study consistently demonstrated a lower L-NAME plateau while using oral contraceptives (∼8%CVC max mean difference) comparable to the mean ∼8%CVC max reduction in the L-NAME plateau in oral contraceptive users compared with non-users in the authors' recent cross-sectional study   (Lee et al., 2022)' . Indeed, Lee et al. (2022) observed that previous oral contraceptive use was associated with an increased risk for hypertension later in life (probably attributable to the sympathetic and resultant bloodpressure-modulating effects of older oral contraceptives). Conversely, epidemiological data in post-menopausal women indicate that previous oral contraceptive use might also protect against atherosclerosis, a disease closely related to endothelial and vascular function (Shufelt & Bairey Merz, 2009; oral contraceptive types/dosages unknown).
Although data are sparse and there are important socio-economic considerations when interpreting these epidemiological findings, this provides additional, albeit indirect, evidence for the beneficial effects of oral contraceptives on the nitric oxide response and smooth muscle function discussed above. This sentiment is also supported by the exploratory subgroup analysis of oral contraceptive users and non-users in the authors' recent publication , whereby mean differences in all measured outcomes, including those that were not statistically significant, were directionally in accord with oral contraceptive use having beneficial vascular effects. It is worth noting, however, that these long-term Newer-generation progestins might also mitigate the increase in hypertension risk traditionally associated with oral contraceptive pills, because they instead appear to decrease blood pressure (drospirenone; Shufelt & Bairey Merz, 2009) (2023) have exposed an important research gap that will spur future prospective studies and provide valuable evidence to aid women and healthcare providers in making better-informed decisions when balancing the positive and negative effects associated with specific dose and progestin-type combinations.
We close this letter by acknowledging the importance of the authors' work. As noted by Turner, Stanhewicz, Nielsen, Otis et al.
(2023), 75%-85% of women globally use oral contraceptives at some point during their premenopausal years, yet the mechanisms underpinning modulated vascular function with cessation of long-term use have been largely unexplored. This case report provides important hypothesis-building data to support the additional investigation of this topic, which we commend the authors for highlighting and strongly believe is deserving of further attention.

AUTHOR CONTRIBUTIONS
Nathalie V. Kirby drafted the manuscript; all authors provided critical edits and revisions and approved the final version of the manuscript.