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Dural O, Ulusoy HE, Tikiz MA, Gurbanova T, Yasa C, Ugurlucan FG, Akhan SE. JPAG 2022; VOLUME 35, ISSUE 6, P634-637, December, 2022 1. What are the limitations of methodology choice for this study? This retrospective study of 43 girls ages 15 to 24 years with hypogonadism compared bone density in those who had received oral versus transdermal estradiol replacement. While the authors do not specifically state Tanner staging of their cohort, readers can assume patients have completed pubertal development as the authors mention girls with primary amenorrhea first underwent puberty induction with only estrogen, which was started at low dose and gradually increased. Girls were selected if they had an initial dual-energy X-ray absorptiometry of -1 or lower. Both groups showed an improvement in lumbar spine bone density at two years, with transdermal estrogen replacement potentially superior to oral administration. First, the introductory paragraph of the methods section commented that the study group was in a “permanent state of hypogonadism.” That sentence should have been defined up front as excluding those with restrictive eating disorders or other hypothalamic stress that could be reversible with refeeding. Contraceptive needs were also not addressed in the selection of patients or discussed up front as a consideration. From a methodology standpoint, this retrospective chart review does not establish causality, merely correlation. It has two experimental groups, one receiving 2 mg of oral E2 replacement with cyclic progesterone, and the second receiving 0.1 mg of transdermal E2 replacement with cyclic progesterone, without stating that in Turkey, such prescribing would be part of the standard of care, with appropriate reference. The study would have been stronger with a control group who received no estrogen, but if that was not the standard of care, then that exclusion should have been noted up front. 2. How was calcium and vitamin D intake ascertained and monitored? What about compliance with oral versus transdermal E2? A.The limitations of patient recall can be noted. The study also did not follow serum estradiol levels or other marker of compliance, to help determine whether transdermal route patients had better compliance than those taking oral formulations, impacting their trend towards greater bone gains. 3. Comment on the available progestins and estrogens used. Are those formulations available in the US? Europe? South America? Is use of those formulations available and standard at your institution? Formulations may vary in transdermal and oral forms. With the variety of formulations available, clinicians within an institution may use varying regimens. Regimens may depend in part to patient preference (such as oral vs transdermal) and side effects (such as irritation or an adhesive reaction). 4. What are the generalizable findings from this study? Could these findings be generalized to natal females of similar age with reversible hypogonadism, as occurs with restrictive eating disorders or the stress of chronic disease? Why or why not? What further research does this study suggest or inspire? The study affirms previous literature in that physiologic dosing of estrogen is helpful in the management of hypogonadism, and transdermal estrogen is superior to oral. Physiologic dosing of estrogen is similarly advised for use in patients with restrictive eating disorders or the stress of chronic disease, though bone accrual may remain reduced in the setting of low leptin and high cortisol levels, for example. Additionally, those with restrictive eating disorders are encouraged restoration of menses with increasing caloric intake and decreasing exercise, thus hormone replacement therapy may be limited in duration than one with hypogonadism that is irreversible. 5. In the closing paragraph of the manuscript, the authors propose that “Large-scale randomized controlled trials are required to confirm our findings ….” Did the authors provide all the necessary assumptions for readers to calculate a sample size for such a study? A. Four components are necessary to calculate sample size:
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