Estrogen‐Containing Oral Contraceptives Are Associated With Polycystic Liver Disease Severity in Premenopausal Patients

Abstract

The association between estrogen‐containing oral contraceptives and history of pregnancies with disease severity in women with polycystic liver disease (PLD) is unclear. We performed a cross‐sectional cohort study to assess this association by selecting female patients with PLD of which imaging was available prior to any liver volume‐reducing therapy. Patients received a questionnaire to collect detailed information on estrogen use and pregnancies. Preplanned subgroup analyses were performed on premenopausal and postmenopausal patients. The questionnaire was returned by 287 of 360 selected patients (80%). There was no significant association between estrogen‐containing oral contraceptives and height‐adjusted total liver volume (hTLV) in the total group (P = 0.06) and postmenopausal subgroup (P = 0.7). By contrast, each year of exposure corresponds with a 1.45% higher hTLV (P = 0.02) in the premenopausal subgroup, equivalent to a 15.5% higher hTLV for every 10 years of use. Pregnancy duration was not associated with hTLV. In conclusion, patients with PLD should avoid exogenous estrogens.

Estrogens in polycystic liver disease: A target for future therapies?

“…Differences in disease severity between males and females could be caused by genetic differences, epigenetic differences and by differences in hormone levels. It is known that estrogen supplementation stimulates growth 18,19 . In addition, recent data suggest that liver growth does not follow a linear pattern with age, as was previously thought, but liver volumes spontaneously decrease after menopause in female patients 20 .…”

“…Sixty‐four articles were retrieved. All titles and relevant abstracts were read and 9 articles were selected for review 18,19,21–27 . The other 53 were not relevant for this review, see Supplementary Table for specific reasons.…”

New insights into targeting hepatic cystogenesis in autosomal dominant polycystic liver and kidney disease

“…Hormonal replacement therapy with conjugated estrogens in 19 post-menopausal ADPKD patients was associated with an increase in TLV, compared to a volume reduction in controls [56]. In addition, a recent large cross-sectional cohort study showed that every 10 years of oral contraceptive use in premenopausal women was correlated with a 15.5% higher heightadjusted TLV compared to unexposed women [57]. These findings led to the clinical advice to discourage the use of exogenous estrogens in female PLD patients.…”

“…We believe that the female hormone pathway is the most promising future therapeutic target due to several reasons: 1. the majority of PLD patients are female [1]; 2. female patients express a more severe phenotype compared to males [13,56]; 3. growth of polycystic liver declines after menopause [3,53]; 4. exogenous estrogens are a risk factor for hepatic cyst growth in PLD [57]; and 5. postmenopausal hormone administration increases cyst volume [56]. Altogether, these arguments suggest that inducing a post-menopausal status in female PLD patients, for example with GnRH agonists, would be a logical next step.…”

Peer Review #1 of "The reproductive inhibitory effects of levonorgestrel, quinestrol, and EP-1 in Brandt’s vole (Lasiopodomys brandtii) (v0.1)"

“…Although fertility control agents, such as oestrogen and triptolide, can cause temporary infertility in animals, they can be toxic (Kejuan et al 2007;Lipschutz et al 1966;Maier & Herman 2001;van Aerts et al 2019;Xu et al 2019;Yuan et al 2019) and can cause death at higher dosages (Lehmann et al 1989;Zhang et al 2015;Zhang 2015). Therefore, it is important to estimate the toxicity in animals prior to using fertility control agents (Ettlin & Prentice 2002;Gao & Short 1993;Ratti et al 2015;Turner et al 2011;Zhang et al 2015).…”