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

Cushing's syndrome

(1997). Human Cytochrome P450 Enzymes: A Status Report Summarizing Their Reactions, Substrates, Inducers, and Inhibitors. Drug Metabolism Reviews: Vol. 29, No. 1-2, pp. 413-580.

Human Cytochrome P450 Enzymes: A Status Report Summarizing Their Reactions, Substrates, Inducers, and Inhibitors

Aging in men is accompanied by a progressive, but individually variable decline of serum testosterone production, more than 20% of healthy men over 60 yr of age presenting with serum levels below the range for young men. Albeit the clinical picture of aging in men is reminiscent of that of hypogonadism in young men and decreased testosterone production appears to play a role in part of these clinical changes in at least some elderly men, the clinical relevancy of the age-related decline in sex steroid levels in men has not been unequivocally established. In fact, minimal androgen requirements for elderly men remain poorly defined and are likely to vary between individuals. Consequently, borderline androgen deficiency cannot be reliably diagnosed in the elderly, and strict differentiation between “substitutive” and “pharmacological” androgen administration is not possible. To date, only a few hundred elderly men have received androgen therapy in the setting of a randomized, controlled study, and many of th...

https://www.hormonebalance.org/images/documents/Kauffman%2005%20TDS%20REVIEW%20ER.pdf

The decline of androgen levels in elderly men and its clinical and therapeutic implications.

This chapter is an update of the data on substrates, reactions, inducers, and inhibitors of human CYP enzymes published previously by Rendic and DiCarlo (1), now covering selection of the literature through 2001 in the reference section. The data are presented in a tabular form (Table 1) to provide a framework for predicting and interpreting the new P450 metabolic data. The data are formatted in an Excel format as most suitable for off-line searching and management of the Web-database. The data are presented as stated by the author(s) and in the case when several references are cited the data are presented according to the latest published information. The searchable database is available either as an Excel file (for information contact the author), or as a Web-searchable database (Human P450 Metabolism Database, www.gentest.com) enabling the readers easy and quick approach to the latest updates on human CYP metabolic reactions.

Summary of information on human cyp enzymes: human p450 metabolism data

BONE differs from reproductive tissues in that many aspects of skeletal growth, turnover, and function occur in the absence of gonadal hormones. Nevertheless, sex steroids have an important impact on bone physiology: they participate in the sexual dimorphism of the skeleton, play a role in maintenance of mineral homeostasis during reproduction, and are essential to maintaining bone balance in adults. Insufficient levels of certain sex steroids predispose the human skeleton to bone loss and to osteoporotic fractures. Estrogen appears to be the most important sex steroid in preventing osteoporosis in women and is the subject of this review. Serious difficulties must be overcome to understand the action of estrogen on mineralized tissues. The skeleton is heterogeneous and contains many cell types. The cells that synthesize (osteoblasts), lie within (osteocytes), and degrade (osteoclasts) bone matrix are present in small numbers, are difficult to isolate as pure populations, and probably do not proliferate.

Skeletal Effects of Estrogen

Ketoconazole, a broad-spectrum, antifungal drug that is administered orally, has been shown to inhibit sterol synthesis in fungi. When gynecomastia developed in some patients taking this d...

Ketoconazole Blocks Adrenal Steroid Synthesis

• Ketoconazole, a new oral drug used to treat systemic and superficial mycoses, inhibits sterol synthesis in fungi. The development of gynecomastia in two patients prompted us to investigate the effect of the drug on testosterone production. After a 200-, 400-, or 600-mg dose, volunteer male testosterone serum concentrations fell markedly, but returned toward baseline eight to 24 hours later as ketoconazole serum concentrations waned. A marked but transient drop in testosterone levels occurred in patients receiving long-term therapy, and continuous testosterone depression was noted in one. A block of synthesis was demonstrated in vitro. Ketoconazole at concentrations achievable in serum with currently used doses blocked basal and gonadotropin-stimulated testosterone production by rat Leydig cells. The diminution of testosterone synthesis could be significant as further therapeutic trials may use larger doses or more than once-daily administration. The paucity of reports of endocrinologic toxicity may relate to the "escape" from the block demonstrated in vivo. (Arch Intern Med1982;142:2137-2140)

https://jamanetwork.com/journals/INTEMED/articlepdf/602584/archinte_142_12_015.pdf

Ketoconazole Blocks Testosterone Synthesis

• Ketoconazole, an oral antifungal, when given in conventional doses, transiently blocks testosterone synthesis and adrenal response to corticotropin. Higher therapeutic doses (ie, 800 to 1,200 mg/day), even once daily, caused more prolonged blockade. In some men, the serum testosterone concentrations were always subnormal. Bound and free testosterone values were equally diminished. Oligospermia and azospermia after prolonged therapy were noted. Impotence and decreased libido were found. Gynecomastia appeared more common than with lower doses. Depressed response to corticotropin was pronounced. Urine cortisol excretion was depressed. The blockade appeared related to the serum ketoconazole concentration. Instances of normal hormone levels or responsiveness were associated with low ketoconazole concentrations. The hormonal effects were generally unrelated to duration of therapy, although there may have been partial reversal with continued therapy. These effects appeared reversible with discontinuation of therapy. Patients receiving ketoconazole should be considered potentially unable to mount an adrenal stress response and may require testosterone supplementation. ( Arch Intern Med 1984;144:2150-2153)

High-Dose Ketoconazole Therapy and Adrenal and Testicular Function in Humans

Fourteen postmenopausal women with mild hyperparathyroidism were given conjugated estrogens. Serum calcium levels became normal and urinary calcium excretion was reduced for up to 2 years in ten patients taking an average dose of 1.25 mg of estrogen daily. Hypercalcemia returned quickly when therapy was interrupted. Estrogen did not systematically alter serum immunoreactive parathyroid hormone or calcitriol levels or urinary excretion of cyclic adenosine monophosphate. Significant reductions in urinary hydroxyproline and serum alkaline phosphatase activity during estrogen therapy indicate that the major effect of therapy was to decrease bone turnover. Iliac crest biopsy specimens taken before estrogen therapy showed normal trabecular bone volume and excessive osteoid seams. Follow-up biopsy specimens were taken from six patients after 1 year on therapy. Bone volume remained stable, but hyperosteoidosis had improved in only one patient. Without understanding the long-term impact of untreated mild hyperparathyroidism on bone, the benefits of estrogen therapy on bone remain uncertain. However, therapy with conjugated estrogens provides sustained control of serum and urine calcium in most women with hyperparathyroidism and is a reasonable alternative in patients who are not surgical candidates.

Conjugated Estrogens in the Treatment of Postmenopausal Women with Hyperparathyroidism

• Ketoconazole, an antifungal drug, causes gynecomastia in some patients It also inhibits androgen and glucocorticoid synthesis In four volunteer male subjects, 600-mg doses of ketoconazole depressed serum testosterone concentrations markedly, but serum estradiol to a much lesser degree The bound and free percentages of both hormones were not significantly altered The net result was a significant elevation of the estradiol-testosterone ratio, expressed as either total circulating hormone or free hormone In five male patients receiving long-term high-dose ketoconazole therapy, the testosterone concentrations fell, but the effect on estradiol was variable In these patients the estradiol-testosterone ratio was persistently increased Since gynecomastia appears to be the result of an elevated estradiol-testosterone ratio, the selective hormonal effect demonstrated may explain the side effect of gynecomastia after ketoconazole therapy (Arch Intern Med1985;145:1429-1431)

Allan Pont

Papers

Ketoconazole Blocks Adrenal Steroid Synthesis

Ketoconazole Blocks Testosterone Synthesis

High-Dose Ketoconazole Therapy and Adrenal and Testicular Function in Humans

Conjugated Estrogens in the Treatment of Postmenopausal Women with Hyperparathyroidism

Ketoconazole-Induced Increase in Estradiol-Testosterone Ratio: Probable Explanation for Gynecomastia