Carrie J. Bagatell

Physiologic testosterone levels in normal men suppress high-density lipoprotein cholesterol levels.

OBJECTIVE To investigate the role of physiologic levels of testosterone in the control of lipoproteins in healthy men. DESIGN A double-blind, randomized study. SETTING A university community. PARTICIPANTS Fifteen healthy men, ages 20 to 36 years. INTERVENTION We induced acute, reversible hypogonadism in five normal men by administering daily subcutaneous injections of the gonadotropin-releasing-hormone (GnRH) antagonist, Nal-Glu, for 6 weeks. Another group of five normal men received Nal-Glu plus weekly injections of testosterone enanthate, 100 mg/wk, thereby maintaining normal serum testosterone levels. Five additional men received placebo injections. MEASUREMENTS Plasma lipids, including high-density lipoprotein (HDL) subfractions HDL2 and HDL3, apoprotein A1, and serum levels of gonadotropins, estradiol, and testosterone were measured before, during, and after treatment. RESULTS At the end of the treatment period, HDL cholesterol levels in men receiving Nal-Glu increased by 26% (95% CI, 18% to 34%; P less than 0.05). Levels of HDL2, HDL3, and apoprotein A1 increased by 63% (CI, 16% to 110%), 17% (CI, 3% to 31%), and 17% (CI, 5% to 29%), respectively (P less than 0.05 for each parameter). Total cholesterol increased by 12% (CI, 2% to 22%). Low-density lipoprotein (LDL) cholesterol and triglyceride concentrations did not change. No statistically significant changes occurred in any lipid measurement in men receiving Nal-Glu plus androgen replacement or placebo (P greater than 0.05). CONCLUSIONS Experimental hypogonadism induced by administration of a GnRH antagonist results in a statistically significant increase in HDL cholesterol, including HDL2 and HDL3. These effects are most likely due to decreased androgen levels because they are reversed by administration of antagonist together with testosterone. Our results imply that androgen levels in the normal adult male range have a suppressive effect on HDL cholesterol concentration and may contribute to the increased risk for coronary artery disease in men.

Androgen and progestagen effects on plasma lipids

Androgens are 19-carbon steroid rings. Progestagens include both 19-carbon and 21-carbon steroid rings; the 19-carbon progestagens are generally more androgenic than are the 21-carbon compounds. Both androgens and progestagens are physiological regulators of plasma lipids, particularly high-density lipoprotein (HDL) cholesterol. The structure of a particular hormonal preparation, as well as its route of administration, modulates its regulatory effects. Both endogenous and exogenous androgens have a suppressive effect on HDL cholesterol in males, with little effect on other plasma lipoproteins. Oral and nonaromatizable androgens have a greater suppressive effect on HDL cholesterol, particularly on HDL2, than do aromatizable androgens. Cross-sectional studies in males generally show a positive relationship between serum T and plasma HDL levels; data in females suggest an inverse relationship between androgens and HDL cholesterol. Medroxy-progesterone acetate and related progestagens have a mild suppressive effect on plasma HDL levels. The C-19 compounds have a greater suppressive effect on HDL cholesterol and the HDL2 density subfraction.

Sperm counts and reproductive hormones in male marathoners and lean controls

In women, chronic and intense endurance exercise is frequently associated with menstrual cycle alterations. In men, the effects of similar amounts of exercise are less well-studied. We tested the hypothesis that endurance exercise in men is also associated with alterations in reproductive function. We studied 12 marathon runners and 12 age-matched, lean controls; serum and semen samples were collected every 2 weeks for 12 weeks. Sperm counts, sperm morphologies, and mean levels of testosterone (T), free T, sex hormone binding globulin, cortisol, follicle-stimulating hormone, and biologically active luteinizing hormone (LH) were similar in the two groups. Mean levels of immunologically active LH were somewhat higher in the marathoners. We conclude that this level of strenuous, long-term endurance exercise does not have major adverse effects on reproductive function in men.

Testosterone-induced suppression of lipoprotein(a) in normal men; relation to basal lipoprotein(a) level

The concentration of lipoprotein(a) [Lp(a)] in human plasma is largely genetically determined and is inversely correlated to the size of apolipoprotein(a) [apo(a)]. Additionally, Lp(a) values are relatively stable within individuals and are only marginally susceptible to therapeutic treatment. The aim of our study was to evaluate the effect of exogenous testosterone on plasma Lp(a) concentration. The study was carried out on 19 healthy men who were receiving weekly intramuscular injections of 200 mg testosterone enanthate. Lp(a) values were determined at multiple time-points by a double monoclonal antibody-based enzyme immunoassay. This method is not sensitive to variation in Lp(a) size and the values are expressed in nmol/l. Apo(a) size isoforms were determined by agarose gel electrophoresis followed by immunoblotting. No correlation was found between the baseline Lp(a) values and the baseline values of testosterone or estradiol. The Lp(a) response to testosterone treatment varied widely among subjects and was dependent upon the pretreatment Lp(a) concentration. For 10 subjects with low Lp(a) values (< 25 nmol/l), no significant decrease in Lp(a) was observed while, for the nine individuals with Lp(a) values > 25 nmol/l, there was a significant and consistent reduction in Lp(a) ranging from 25 to 59%. Lp(a) levels returned to baseline values following cessation of testosterone administration. Apo(a) size polymorphism did not appear to play a role in the determination of Lp(a) response to testosterone.

Single-dose administration of the gonadotropin-releasing hormone antagonist, Nal-Lys (antide) to healthy men

OBJECTIVE To evaluate the ability the Nal-Lys GnRH antagonist ([N-Ac-Nal (2)1, 4ClDPhe2, D3Pal3, Lys (Nic)5, D-Lys(Nic)6, Lys (iPr)8, D-Ala10] to suppress gonadotropins and T in humans and to assess its duration of action and its local effects. DESIGN Placebo-controlled clinical study. SETTING A university community. SUBJECTS Seven normal male volunteers. INTERVENTIONS We administered single injections of Nal-Lys (0, 10, 25, and 50 micrograms/kg body weight). Blood samples were collected before and at frequent time intervals after injection. RESULTS Nal-Lys caused only minor local effects. At the higher doses (25 and 50 micrograms/kg), serum LH and T levels were suppressed to 50% to 70% of baseline; serum FSH levels were suppressed to 70% to 80% of baseline, and levels of all three hormones returned to basal values within 24 hours after injection. CONCLUSIONS In humans, Nal-Lys has similar potency and duration of action to other antagonists and produces fewer local side effects. However, the utility of Nal-Lys is limited by formulation difficulties; current efforts are directed at improving the formulation in order to explore the potential clinical uses of this peptide.

Androgens in health and disease

I. General Andrology Testosterone Synthesis, Transport, and Metabolism Stephen J. Winters and Barbara J. Clark Androgen Action Terry R. Brown Hypogonadism in Men: An Overview Stephen R. Plymate Dihydrotestosterone and 5a-Reductase: Normal Physiology and Inhibition Paul R. Sutton, John K. Amory, and Richard V. Clark Estrogen Action in Males: Insights Through Mutations in Aromatase and Estrogen-Receptor Genes Jonathan Lindzey and Kenneth S. Korach Alterations of Androgen Action Caused by Mutation of the Human Androgen Receptor Michael J. McPhaul Androgen Excess Disorders in Women Richard S. Legro Androgen Pharmacology and Delivery Systems Christina Wang and Ronald S. Swerdloff II. Androgen Effects on Physiologic Systems Androgen Signaling in Prostatic Neoplasia and Hyperplasia Marco Marcelli, Dolores J. Lamb, Nancy L. Weigel, and Glenn R. Cunningham Androgens and Coronary Artery Disease Frederick C. W. Wu and Arnold von Eckardstein Androgens and Bone Anne M. Kenny and Lawrence G. Raisz Androgens and the Hematopoietic System Shehzad Basaria and Adrian S. Dobs Androgens and Body Composition Laurence Katznelson Androgens and Sexual Function in Men and Women John Bancroft Androgens and Cognition Monique M. Cherrier and Suzanne Craft III. Applied Andrology Androgen Treatment of the Hypogonadal Male Alvin M. Matsumoto Androgens and Puberty Erick J. Richmond and Alan D. Rogol Androgens as Anabolic Agents Shalender Bhasin, Linda J. Woodhouse, and Thomas W. Storer Androgens and Male Contraception John K. Amory Androgens in Primary Care Bradley D. Anawalt Index

Preservation of fertility despite subnormal gonadotropin and testosterone levels after cessation of pulsatile gonadotropin-releasing hormone therapy in a man with Kallmann's syndrome.

A man with IHH and anosmia presented in 1980. He was successfully treated with various hormonal regimens; four children were conceived with hCG or pulsatile GnRH therapy. The patient discontinued GnRH after the fourth child was conceived, and testosterone enanthate injections were prescribed. However, he took the injections only briefly and 15 months later he demonstrated continuing spermatogenesis despite low serum FSH and LH levels. His wife successfully became pregnant. This case adds to the recognized range of recovery in IHH, with fertility despite stopping hormonal therapy and despite low serum gonadotropin and T levels.

Dose effects of the gonadotropin-releasing hormone antagonist, Nal-Glu, combined with testosterone enanthate on gonadotropin levels in normal men*

OBJECTIVE To test the hypothesis that over a 4-week treatment period, Nal-Glu GnRH antagonist ([AcD2Nal1, D4ClPhe2, D3Pal3, Arg5, DGlu6 [AA], DAla10] GnRH) at a dose of 200 micrograms/kg per day SC would suppress levels of immunologically active and biologically active LH and FSH more completely than a dose of 100 micrograms/kg per day. DESIGN Placebo controlled clinical study. SETTING A university community. SUBJECTS Thirty normal male volunteers. INTERVENTIONS We administered Nal-Glu at doses of 0, 100, and 200 micrograms/kg body weight per day in combination with T enanthate, 50 mg IM weekly, to separate groups of men (9 or 10 men per group) for 4 weeks. RESULTS Serum levels of immunologically active and biologically active gonadotropins were suppressed similarly in both groups of men who received Nal-Glu; this suppression was significantly greater than in the men who received placebo + T. Local side effects were more severe in the Nal-Glu 200 micrograms/kg per day group. CONCLUSIONS Administration of Nal-Glu in combination with T suppresses gonadotropins more completely than does T alone, but at doses > 100 micrograms/kg, gonadotropins are not suppressed additionally with larger doses of Nal-Glu. Subjects experienced greater local discomfort and side effects with the higher dosage. These findings suggest that dosages of Nal-Glu of > 100 micrograms/kg per day may have no advantage over the 100-micrograms/kg dose in a male contraceptive regimen.

Androgen and Estrogen Effects on Plasma Lipids in Men

It is widely appreciated that premenopausal women have a lower risk for coronary artery disease (CAD) than do men, and that this risk increases in postmenopausal women (1,2).The effects of estrogens on plasma lipids and other factors affecting coronary risk in women have been studied extensively, and are reviewed elsewhere (3–5). The contributions of gonadal steroids to coronary risk in men have received less attention. This chapter reviews the effects of androgens and estrogen on plasma lipids and relates these data to the increased coronary risk associated with male gender.