https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)61375-1.pdf

Cushing's syndrome

In many nonprimate mammalian species, cyclical regression of the corpus luteum (luteolysis) is caused by the episodic pulsatile secretion of uterine PGF2α, which acts either locally on the corpus l...

Luteolysis: A Neuroendocrine-Mediated Event

Publisher Summary This chapter discusses some of the physiological and pathophysiological actions of hormones in controlling the development of the sexual phenotypes of eutherian mammals, the American opossum, and the chicken. The importance of steroid metabolites formed in extraglandular tissues to overall sexual development is also emphasized. Chromosomal sex determines gonadal sex, and gonadal sex determines phenotypic sex. A minimum of 19 genes are implicated in sexual differentiation in man. Some of these are located on sex chromosomes and some on autosomes. Thus, the relatively simple mechanism that imposes male development on the indifferent embryo requires the participation of many genes common to both the male and female embryo. Determinants on the Y chromosome cause the indifferent gonad to develop into a testis. Two hormonal secretions from the fetal testis, mullerian-inhibiting substance and testosterone, then transform the indifferent urogenital tract into one characteristic of the male. Mullerian-inhibiting substance secreted by the Sertoli cells causes regression of the female duct system.

https://science.sciencemag.org/content/sci/211/4488/1278.full.pdf

The hormonal control of sexual development

The aim of this review is to provide an integrative analysis of the role of FSH in the control of testicular function in higher primates, including man. Attention is focused on the action of FSH during neonatal development, puberty, and adulthood. Whether FSH is the major determinant of the adult complement of Sertoli cells and whether FSH is obligatory for the initiation, maintenance, and restoration of spermatogenesis is evaluated. The mechanism whereby the circulating concentration of FSH regulates spermatogonial proliferation to dictate the sperm production rate under physiological conditions in the adult is discussed in detail. Inhibin B is the major component of the testicular negative feedback signal governing FSH beta gene expression and FSH secretion, and the evidence for this view is presented. The review concludes with the presentation of a model for the operation of the FSH-inhibin B feedback control system regulating sperm production postpubertally in monkey and man, and with speculation on issues of clinical interest.

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The Functional Significance of FSH in Spermatogenesis and the Control of Its Secretion in Male Primates

Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.

The Treatment of Cushing's Disease

In dogs receiving oral treatment with 2,2-bis (2-chlorophenyl-4-chlorophenyl)- l,l-dichloroethane (o,p' DDD) for periods of 2, 4, and 6 days, the secretion rate of 17-hydroxycorticosteroids was markedly decreased. Histological observations on the adrenal cortex showed that focal degenerative lesions developed first in the zona reticularis, then in the zona fasciculata. No changes were seen in the zona glomerulosa even after 6 days treatment. Morphological changes in the zona reticularis and zona fasciculata were slight after 2 days treatment although there was alreacty a marked reduction in the digitoninprecipitable compounds of these zones. After 6 days treatment, 3β-hydroxy sterols were almost absent from the zona fasciculata and zona reticularis. Distribution of sudanophilic lipids of these zones remained unaltered during this period.

Effects of o,p' DDD on histology and 17-hydroxycorticosteroid output of the dog adrenal cortex.

The synthesis of testosterone from pregnenolone and androstenedione was measured at several intervals during gestation and after parturition. Testosterone synthesis was demonstrated in the fetal testis on the eighteenth day of gestation before Leydig cells could be identified. The extent of conversion of pregnenolone to testosterone increased during gestation and decreased after parturition. At all points, the fetal testis had a greater capacity for testosterone synthesis than did the fetal ovary. (Endocrinology 77:273, 1965)

Testosterone Synthesis by the Fetal Rabbit Gonad

/pdf/fetal-or-material-hypophysectomy-in-rhesus-monkeys-macaca-5fjai65nk4.pdf

Fetal or Material Hypophysectomy in Rhesus Monkeys (Macaca mulatta): Effects on the Development of Testes and Other Endocrine Organs

Concentrations of macaque chorionic gonadotropin (mCG) in placenta, blood and urine of rhesus monkeys have been measured by both radioimmunoassay and bioassay throughout gestation. mCG was easily detected and quantified in these specimens for a brief period in early pregnancy, but was not detectable between the 40th day of pregnancy and term in placental extracts, serum, or 40-fold urine concentrates. The apparent absence of mCG after the 40th day of pregnancy makes these macaques a valuable model for pregnancy research, where the absence of chorionic gonadotropin is experimentally desirable. Unlike women and some higher primates, the functional status of the fetal, placental and maternal endocrine compartments of macaques can be studied in the absence of circulating chorionic gonadotropin during mid and late gestation. (Endocrinology 96: 789, 1975)

William W. Tullner

Papers

Effects of o,p' DDD on histology and 17-hydroxycorticosteroid output of the dog adrenal cortex.

Testosterone Synthesis by the Fetal Rabbit Gonad

Fetal or Material Hypophysectomy in Rhesus Monkeys (Macaca mulatta): Effects on the Development of Testes and Other Endocrine Organs

Duration of chorionic gonadotropin production by the placenta of the rhesus monkey.

Inhibition of estrogen-induced tissue growth with progesterone.