The Relationship Between Bone and Reproductive Hormones Beyond Estrogens and Androgens 

Edouard G Mills, Lisa Yang, Morten F Nielsen, Moustapha Kassem, Waljit S Dhillo, Alexander N Comninos

doi : 10.1210/endrev/bnab015

Endocrine Reviews, Volume 42, Issue 6, December 2021, Pages 691–719

Reproductive hormones play a crucial role in the growth and maintenance of the mammalian skeleton. Indeed, the biological significance for this hormonal regulation of skeletal homeostasis is best illustrated by common clinical reproductive disorders, such as primary ovarian insufficiency, hypothalamic amenorrhea, congenital hypogonadotropic hypogonadism, and early menopause, which contribute to the clinical burden of low bone mineral density and increased risk for fragility fracture. Emerging evidence relating to traditional reproductive hormones and the recent discovery of newer reproductive neuropeptides and hormones has deepened our understanding of the interaction between bone and the reproductive system. In this review, we provide a contemporary summary of the literature examining the relationship between bone biology and reproductive signals that extend beyond estrogens and androgens, and include kisspeptin, gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, progesterone, inhibin, activin, and relaxin. A comprehensive and up-to-date review of the recent basic and clinical research advances is essential given the prevalence of clinical reproductive disorders, the emerging roles of upstream reproductive hormones in bone physiology, as well as the urgent need to develop novel safe and effective therapies for bone fragility in a rapidly aging population.

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Hormone Therapy in Menopause: Concepts, Controversies, and Approach to Treatment

Valerie A Flores, Lubna Pal, JoAnn E Manson

doi : 10.1210/endrev/bnab011

Endocrine Reviews, Volume 42, Issue 6, December 2021, Pages 720–752

Hormone therapy (HT) is an effective treatment for menopausal symptoms, including vasomotor symptoms and genitourinary syndrome of menopause. Randomized trials also demonstrate positive effects on bone health, and age-stratified analyses indicate more favorable effects on coronary heart disease and all-cause mortality in younger women (close proximity to menopause) than in women more than a decade past menopause. In the absence of contraindications or other major comorbidities, recently menopausal women with moderate or severe symptoms are appropriate candidates for HT. The Women’s Health Initiative (WHI) hormone therapy trials—estrogen and progestin trial and the estrogen-alone trial—clarified the benefits and risks of HT, including how the results differed by age. A key lesson from the WHI trials, which was unfortunately lost in the posttrial cacophony, was that the risk:benefit ratio and safety profile of HT differed markedly by clinical characteristics of the participants, especially age, time since menopause, and comorbidity status. In the present review of the WHI and other recent HT trials, we aim to provide readers with an improved understanding of the importance of the timing of HT initiation, type and route of administration, and of patient-specific considerations that should be weighed when prescribing HT.

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Anti-Müllerian Hormone in Female Reproduction

Nathalie di Clemente, Chrystèle Racine, Alice Pierre, Joëlle Taieb

doi : 10.1210/endrev/bnab012

Endocrine Reviews, Volume 42, Issue 6, December 2021, Pages 753–782

Anti-Müllerian hormone (AMH), also called Müllerian inhibiting substance, was shown to be synthesized by the ovary in the 1980s. This article reviews the main findings of the past 20 years on the regulation of the expression of AMH and its specific receptor AMHR2 by granulosa cells, the mechanism of action of AMH, the different roles it plays in the reproductive organs, its clinical utility, and its involvement in the principal pathological conditions affecting women. The findings in respect of regulation tell us that AMH and AMHR2 expression is mainly regulated by bone morphogenetic proteins, gonadotropins, and estrogens. It has now been established that AMH regulates the different steps of folliculogenesis and that it has neuroendocrine effects. On the other hand, the importance of serum AMH as a reliable marker of ovarian reserve and as a useful tool in the prediction of the polycystic ovary syndrome (PCOS) and primary ovarian failure has also been acknowledged. Last but not least, a large body of evidence points to the involvement of AMH in the pathogenesis of PCOS.

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Normal and Premature Adrenarche 

Robert L Rosenfield

doi : 10.1210/endrev/bnab009

Endocrine Reviews, Volume 42, Issue 6, December 2021, Pages 783–814

Adrenarche is the maturational increase in adrenal androgen production that normally begins in early childhood. It results from changes in the secretory response to adrenocorticotropin (ACTH) that are best indexed by dehydroepiandrosterone sulfate (DHEAS) rise. These changes are related to the development of the zona reticularis (ZR) and its unique gene/enzyme expression pattern of low 3ß-hydroxysteroid dehydrogenase type 2 with high cytochrome b5A, sulfotransferase 2A1, and 17ß-hydroxysteroid dehydrogenase type 5. Recently 11-ketotestosterone was identified as an important bioactive adrenarchal androgen. Birth weight, body growth, obesity, and prolactin are related to ZR development. Adrenarchal androgens normally contribute to the onset of sexual pubic hair (pubarche) and sebaceous and apocrine gland development. Premature adrenarche causes ?90% of premature pubarche (PP). Its cause is unknown. Affected children have a significantly increased growth rate with proportionate bone age advancement that typically does not compromise growth potential. Serum DHEAS and testosterone levels increase to levels normal for early female puberty. It is associated with mildly increased risks for obesity, insulin resistance, and possibly mood disorder and polycystic ovary syndrome. Between 5% and 10% of PP is due to virilizing disorders, which are usually characterized by more rapid advancement of pubarche and compromise of adult height potential than premature adrenarche. Most cases are due to nonclassic congenital adrenal hyperplasia. Algorithms are presented for the differential diagnosis of PP. This review highlights recent advances in molecular genetic and developmental biologic understanding of ZR development and insights into adrenarche emanating from mass spectrometric steroid assays.

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Multi-organ Coordination of Lipoprotein Secretion by Hormones, Nutrients and Neural Networks

Priska Stahel, Changting Xiao, Avital Nahmias, Lili Tian, Gary Franklin Lewis

doi : 10.1210/endrev/bnab008

Endocrine Reviews, Volume 42, Issue 6, December 2021, Pages 815–838

Plasma triglyceride-rich lipoproteins (TRL), particularly atherogenic remnant lipoproteins, contribute to atherosclerotic cardiovascular disease. Hypertriglyceridemia may arise in part from hypersecretion of TRLs by the liver and intestine. Here we focus on the complex network of hormonal, nutritional, and neuronal interorgan communication that regulates secretion of TRLs and provide our perspective on the relative importance of these factors. Hormones and peptides originating from the pancreas (insulin, glucagon), gut [glucagon-like peptide 1 (GLP-1) and 2 (GLP-2), ghrelin, cholecystokinin (CCK), peptide YY], adipose tissue (leptin, adiponectin) and brain (GLP-1) modulate TRL secretion by receptor-mediated responses and indirectly via neural networks. In addition, the gut microbiome and bile acids influence lipoprotein secretion in humans and animal models. Several nutritional factors modulate hepatic lipoprotein secretion through effects on the central nervous system. Vagal afferent signaling from the gut to the brain and efferent signals from the brain to the liver and gut are modulated by hormonal and nutritional factors to influence TRL secretion. Some of these factors have been extensively studied and shown to have robust regulatory effects whereas others are “emerging” regulators, whose significance remains to be determined. The quantitative importance of these factors relative to one another and relative to the key regulatory role of lipid availability remains largely unknown. Our understanding of the complex interorgan regulation of TRL secretion is rapidly evolving to appreciate the extensive hormonal, nutritional, and neural signals emanating not only from gut and liver but also from the brain, pancreas, and adipose tissue.

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ER Stress in Cardiometabolic Diseases: From Molecular Mechanisms to Therapeutics

Amir Ajoolabady, Shuyi Wang, Guido Kroemer, Daniel J Klionsky, Vladimir N Uversky, James R Sowers, Hamid Aslkhodapasandhokmabad, Yaguang Bi, Junbo Ge, Jun Ren

doi : 10.1210/endrev/bnab006

Endocrine Reviews, Volume 42, Issue 6, December 2021, Pages 839–871

The endoplasmic reticulum (ER) hosts linear polypeptides and fosters natural folding of proteins through ER-residing chaperones and enzymes. Failure of the ER to align and compose proper protein architecture leads to accumulation of misfolded/unfolded proteins in the ER lumen, which disturbs ER homeostasis to provoke ER stress. Presence of ER stress initiates the cytoprotective unfolded protein response (UPR) to restore ER homeostasis or instigates a rather maladaptive UPR to promote cell death. Although a wide array of cellular processes such as persistent autophagy, dysregulated mitophagy, and secretion of proinflammatory cytokines may contribute to the onset and progression of cardiometabolic diseases, it is well perceived that ER stress also evokes the onset and development of cardiometabolic diseases, particularly cardiovascular diseases (CVDs), diabetes mellitus, obesity, and chronic kidney disease (CKD). Meanwhile, these pathological conditions further aggravate ER stress, creating a rather vicious cycle. Here in this review, we aimed at summarizing and updating the available information on ER stress in CVDs, diabetes mellitus, obesity, and CKD, hoping to offer novel insights for the management of these cardiometabolic comorbidities through regulation of ER stress.

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Erratum to: “The Relationship Between Bone and Reproductive Hormones Beyond Estrogens and Androgens” 

doi : 10.1210/endrev/bnab024

Endocrine Reviews, Volume 42, Issue 6, December 2021, Page 872

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Erratum to: “Conducting Real-world Evidence Studies on the Clinical Outcomes of Diabetes Treatments” 

doi : 10.1210/endrev/bnab032

Endocrine Reviews, Volume 42, Issue 6, December 2021, Page 873

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