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Endocrine Disorders, Contraception, and Hormone Therapy during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
An 11-hydroxylase inhibitor, metyrapone (Metopirone), causes a decrease in cortisol production, followed by a subsequent rise of deoxycortisol, the immediate precursor of cortisol. In animal studies, metyrapone crosses the placenta (Baram and Schultz, 1990). Metyrapone is used infrequently during late pregnancy as medical therapy for Cushing’s disease to delay surgical intervention until after delivery (Connell et al., 1985b; Gormley et al., 1982). In summary, the ideal therapy for Cushing’s disease in pregnancy is surgical intervention. Metyrapone therapy is used to treat Cushing until delivery or fetal maturity. Surgery is postponed until after delivery. In a rat study, pregnant animals were dosed during organogenesis at about seven times the usual human dose; resorptions occurred in 80 percent of pregnancies treated with the drug (Nevagi and Rao, 1970).
Adrenal insufficiency
Published in Nadia Barghouthi, Jessica Perini, Endocrine Diseases in Pregnancy and the Postpartum Period, 2021
Insulin tolerance testing is contraindicated in pregnancy due to potential risks to the fetus when maternal blood glucose levels are <40 mg/dL. Similarly, the metyrapone stimulation test is not recommended during pregnancy due to the risk of precipitating adrenal crisis.
The Management of Treatment-Resistant Depression
Published in Dr. Ather Muneer, Mood Disorders, 2018
Excess cortisol has been shown to have potent negative effects on mood. Several downstream mechanisms may be at play including the increased activity of indoleamine 2, 3 dioxygenase leading to decreased serotonin and increased levels of TRYCATs (tryptophan catabolites). Therefore, preventing hypercortisolemia may serve as another novel target. Of particular interest has been metyrapone, a cortisol synthesis inhibitor (inhibitor of 11-β hydroxylase, the enzyme that catalyzes the conversion of 11-deoxycortisol to cortisol). Several open-label trials showed a positive effect of metyrapone on TRD. Further, in a RCT with 63 in-patients with severe MDD, augmentation of nefazodone or fluvoxamine for three weeks with placebo versus 1 g of metyrapone once daily was assessed. The metyrapone group showed a significantly greater improvement compared with the placebo group (effect size of 0.6) using response (a decrease in HRSD score by 50%, five weeks post initiation of treatment) as the outcome measure.39 One additional RCT has been completed; however, results are yet to be published. Oxytocin has also been shown to be a potent suppressor of the HPA axis. Intranasal oxytocin is therefore being currently investigated in a RCT for TRD.
Adrenal disorders in pregnancy, labour and postpartum – an overview
Published in Journal of Obstetrics and Gynaecology, 2020
Madhavi Manoharan, Prabha Sinha, Shabnum Sibtain
Medical treatment with anticortisolic drugs remains a second line of treatment (Lim et al. 2013; Touiti and Mghari 2015; Zieleniewski and Michalak 2017). The drugs commonly used are Metyrapone, Ketoconazole, Cyproheptidine, Amino-glutethemide, Mitotane and Cabergoline. They act by inhibiting steroid synthesis. Metyrapone is the most commonly used treatment with no side effects on maternal liver function or foetal development. This has been used in 69% of cases with good control of hyper cortisolism, in most of the cases (Lindsay et al. 2005; Blanco et al. 2006). However, Metyrapone can exacerbate high blood pressure and preeclampsia. Ketoconazole is not advisable in pregnancy because of risk of transplacental passage and its teratogenic and antiandrogenic effects on the fetus. (Berwaerts et al. 1999; Lindsay et al. 2005; Boronat et al. 2011). Mitotane and aminoglutethimide are also contraindicated during pregnancy because of risk of foetal masculinisation and teratogenicity (McClamrock and Adashi 1992). Cabergoline is not commonly used in pregnancy, unless the condition is persistent and recurrent (Woo and Ehsanipoor 2013; Nakhleh et al. 2016; Sek et al. 2017). Medical treatment with anticortisolic drugs could be reserved for special cases, with Metyrapone being the safest option. These drugs should be used with extreme caution in view of the low number of patients reported and limited experience with its use (Brue et al. 2018).
New and emerging drug therapies for Cushing’s disease
Published in Expert Opinion on Pharmacotherapy, 2018
Sylvère Störmann, Jochen Schopohl
In the 1950s, the inhibitor of steroidogenesis, amphenone B, was closely studied and considered as a therapeutic option for CS. Unfortunately, adverse events were common, and many serious side effects limited its use as treatment. To counter these disadvantages, several analogs were developed and tested, one of which was SU-4885, known today as metyrapone [150]. Metyrapone inhibits mostly 11β-hydroxylase and to a lesser extent 18-hydroxylase, thereby reducing cortisol and aldosterone synthesis [151,152]. It was introduced and approved as a diagnostic test agent for CS as early as 1958 in the United States. The EMA has also approved it as a therapeutic agent. There are only small studies on the effectiveness of metyrapone in CS/CD, but normalization of UFC in up to 75% of patients has been reported [153]. In the largest series to date regarding 164 patients with CS on metyrapone monotherapy, more than 80% of patients showed an improvement in levels of circulating cortisol with over 50% achieving biochemical eucortisolemia assessed by cortisol day-curve [154]. In theory, the accumulation of steroid hormone precursors and increases in ACTH levels through the loss of negative feedback should lead to hyperandrogenism; in practice, reports of hirsutism and acne are seldom. The most commonly reported side effect was diffuse gastrointestinal discomfort.
An evaluation of pharmacological options for Cushing’s disease: what are the state-of-the-art options?
Published in Expert Opinion on Pharmacotherapy, 2023
Marianna Martino, Nairus Aboud, Beatrice Lucchetti, Gianmaria Salvio, Giorgio Arnaldi
Conversely, the recent guidelines suggest the use of cabergoline or pasireotide in mild disease and when a residual tumor is detectable, as these drugs may induce tumor shrinkage. Patients treated with pasireotide are at risk to develop diabetes mellitus and require glycemic monitoring. Cabergoline should be avoided if there is a history of bipolar or impulse control disorder. Guidelines consider the use of cabergoline or metyrapone in pregnant women or in those desiring pregnancy even if none of the available drugs for CS are approved in such cases.