Normal Adult Male Range Research Articles

The effect of three-month topical testosterone gel application on semen quality in men with oligozoospermia and low serum testosterone levels

Objective: The effects of daily topical application of testosterone gel on semen characteristics in infertile men with oligozoospermia and hypogonadism were assessed. Methods: Sixteen infertile men were included in this prospective study. A daily morning application of 25 mg transdermal testosterone (T) gel was used for 3 months. Semen parameters, serum follicular stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E) and T levels, and seminal plasma E and T levels were measured before treatment and once monthly for three months during the therapy. Results: The baseline median sperm concentration was 5.5 × 106/mL. Median sperm concentrations at the first, second and third months were 9 × 106, 8 × 10 6, and 4 × 106/mL, respectively. The sperm concentrations at the first and second months after starting therapy significantly (p < 0.001) increased compared with the baseline. However, sperm volume, pH, motility, viability and morphology were similar to baseline. Serum T significantly (p < 0.001) increased, while serum FSH significantly (p < 0.001) decreased from baseline. Seminal T and T/E ratios were raised significantly (p = 0.008 and p = 0.004, respectively) after gel application, whereas the seminal E level was not affected. Conclusions: Daily 25 mg T gel applications for oligospermic infertile men with hypogonadism increased the sperm concentration at the first and second months and raised the serum T level to the normal adult male range. Nevertheless, the sperm concentration had a decreasing trend after the third month.

The impact of sirolimus on sex hormones in male adolescent kidney recipients

While it is known that sirolimus affects sex hormones in adult kidney transplant patients, there is a scarcity of data on its effects on sex hormone levels in adolescent kidney recipients. The objective of this study is to describe the impact of sirolimus on the sex hormones in this patient population. This is a retrospective review of male adolescent renal transplant patients transitioned to sirolimus. Baseline and subsequent annual testosterone levels were collected. Linear regression was undertaken to determine the predictors of testosterone levels. Four African Americans and 11 Caucasians, median age of 15 yr (11-18) in 2008, were included. Mean time post-transplant was 81 ± 37 months. Mean testosterone values were the following: 336 ± 135 ng/dL (n = 8) at baseline, 349 ± 130 ng/dL (n = 15) one yr later, and 360 ± 132 ng/dL (n = 13) two yr later (normal range for adult males: 350-970 ng/dL). Seven (47%) patients experienced a decrease in testosterone levels. Time on sirolimus was associated with decreased testosterone (r = 0.643, p = 0.010). Testosterone levels in pubertal male kidney transplant recipients on sirolimus may be suppressed, especially if they have been treated with sirolimus for several years. These data need to be confirmed in a larger study.

Reversible hypogonadism in Bardet-Biedl syndrome

To report a patient with Bardet-Biedl syndrome (BBS) with known hypogonadotrophic hypogonadism who developed spontaneous reversal of hypogonadism in adulthood. Case report and discussion. Endocrine unit of a tertiary hospital. A 30-year-old male patient with BBS. Clinical evaluation, fine-needle aspiration of the testes, hormonal, cytogenetic, and pathologic evaluation. Serum gonadotropins and testosterone levels and presence of spermatogenesis in testicular aspirate. Serum testosterone and gonadotropin levels were within the normal adult male range. Testicular aspirates showed spermatogenic cells of all series, including numerous spermatozoa and a few intact seminiferous tubules. The overall picture appeared to be consistent with normal spermatogenesis. This is the first case of reversal of hypogonadotrophic hypogonadism in a male patient with BBS. Clinicians should look for such reversal in other patients with hypogonadotrophic hypogonadism and give appropriate prognosis.

Androgens and the ageing male.

Serum testosterone levels peak in early adulthood in men and fall progressively with age. Since sex hormone binding globulin increases with age, the unbound forms of testosterone (free and bioavailable testosterone) fall more steeply than total testosterone levels. Serum testosterone levels below the normal range for young healthy adult males provide chemical evidence of androgen deficiency independent of the age of the patient. When accompanied by signs or symptoms that are compatible with androgen deficiency, treatment with testosterone should be considered in older men without evidence of prostate or breast cancer. While such therapy for younger hypogonadal men has shown benefit on libido, mood, muscle mass, muscle strength, bone mineral density and haematocrit, similar benefits in older men have not been as adequately assessed. While there is no convincing evidence that testosterone treatment in older men will increase the risk of cardiovascular or prostate cancer, long-term, well-controlled studies are lacking and needed. Treatment options for older men include injectable, transdermal and transbuccal testosterone preparations.

Physiological testosterone replacement and arterial endothelial function in men.

The vascular effects of fluctuations in testosterone levels within the physiological range in otherwise healthy men are not known. We therefore aimed to study arterial function in hypogonadal men receiving long-term physiological androgen replacement therapy, at trough and peak testosterone levels. We recruited nine hypogonadal men (aged 35 +/- 4 years) receiving androgen replacement therapy, each treated with 800 mg testosterone (T) depot preparations every 6 months. Serum lipid and hormone levels and arterial reactivity were measured, prior to (trough T) and 2-4 weeks following testosterone administration (peak T). Each subject therefore served as their own control. Vessel diameter was measured by ultrasound at rest, during reactive hyperaemia [leading to flow-mediated dilatation (FMD), an endothelium-dependent response] and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). Serum T (13 +/- 2 nmvs. 27 +/- 3 nm for trough and peak serum T, respectively, P < 0.001; normal adult male range 11-35 nm), and free T (195 +/- 23 pmvs. 510 +/- 93 pm, P < 0.005) significantly increased following subcutaneous depot T administration, as did serum oestradiol (100 +/- 10 pmvs. 175 +/- 9 pm, P = 0.001; normal adult male range < 250 pm). There was a significant decrease in FMD (3.6 +/- 1.1%vs. 3.0 +/- 0.8%, P < 0.01), but GTN responses were similar (9.5 +/- 0.8%vs. 10.4 +/- 1.0%, P > 0.2). Lipid, blood pressure and vessel diameter measurements were also similar before and after testosterone administration. Physiological replacement of testosterone is associated with decreased endothelium-dependent dilatation, in hypogonadal men.

Decreased pituitary-gonadal secretion in men with obstructive sleep apnea.

Decreased libido is frequently reported in male patients with obstructive sleep apnea (OSA). The decline in morning serum testosterone levels previously reported in these patients was within the normal adult male range and does not explain the frequent association of OSA and sexual dysfunction. We determined serum LH and testosterone levels every 20 min between 2200-0700 h with simultaneous sleep recordings in 10 men with sleep apnea and in 5 normal men free of any breathing disorder in sleep. The mean levels and area under the curve of LH and testosterone were significantly lower in OSA patients compared with controls [LH, 24.9 +/- 10.2 IU/liter.h vs. 43.4 +/- 9.5 (P < 0.005); testosterone, 67.2 +/- 11.5 nmol/liter.h vs. 113.3 +/- 26.8 (P < 0.003)]. Four of 10 patients had hypogonadal morning (0700 h) serum testosterone levels. Analysis of covariance (ANCOVA) revealed that the 2 groups differed significantly in the amount of LH and testosterone secreted at night independent of age or degree of obesity. After partialing out body mass index, there was a significant negative correlation between the amounts of LH and testosterone secreted at night and the respiratory distress index, but not with degree of hypoxia. Our findings suggest that OSA in men is associated with dysfunction of the pituitary-gonadal axis. The relation between LH-testosterone profiles and the severity of OSA suggests that sleep fragmentation and, to a lesser extent, hypoxia in addition to the degree of obesity and aging may be responsible for the central suppression of testosterone in these patients.

Importance of Inhibin B in the Regulation of FSH Secretion in the Human Male

Regulation of FSH secretion in the male involves a complex balance between stimulation by GnRH from the hypothalamus, inhibitory feedback by sex steroids (T and E2) and inhibin B (Inh B) from the gonads, and autocrine/paracrine modulation by activin and follistatin within the pituitary. The aim of the present study was to delineate the feedback control of FSH in the human male with specific reference to the relative roles of sex steroids vs. Inh B. Two experimental human models were used: 1) normal (NL) men subjected to acute sex steroid withdrawal (-T, -E2, + Inh B), and 2) functional castrate males (-T, -E2, -Inh B). Nine NL men (age range, 25-45 yr) and three castrate males (age range, 23-47 yr) were studied. The NL men underwent acute sex steroid suppression using high dose ketoconazole (1-g loading dose, followed by 400 mg, orally, four times daily for 150 h). Gonadotropin secretion was characterized by frequent blood sampling every 10 min for 12 h at baseline and on d 3 and 6 of sex steroid ablation. In the three castrate subjects, blood sampling was performed every 5 min for 24 h 8 wk after discontinuing androgen replacement therapy. In the NL men, treatment with ketoconazole resulted in a decline to castrate levels in T (451 +/- 20 to 38 +/- 7 ng/dl; P < 0.0005) and E2 (39 +/- 4 to 15 +/- 2 pg/ml; P < 0.005) and a modest, but significant, decline in Inh B levels, which remained within the normal range (183 +/- 19 to 136 +/- 13 pg/ml; P < 0.005). This suppression of sex steroids was associated with a more marked increase in mean LH (9.5 +/- 0.9 to 24.9 +/- 2.0 IU/liter; P < 0.0001) than FSH levels (5.1 +/- 0.7 to 10.0 +/- 1.5 IU/liter; P < 0.005), with the latter not exceeding the normal adult male range. The castrate subjects had a mean T level of 66 +/- 8 ng/dl, an E2 level of 20 +/- 1 pg/ml, and undetectable Inh B levels. Despite a similar sex steroid milieu, the mean FSH levels observed in NL men after acute sex steroid ablation were approximately 6-fold lower than those seen in the castrate subjects (10.0 +/- 1.5 vs. 59.5 +/- 17.7 IU/liter; P < 0.0005). In contrast, mean LH levels in the NL men were less than 3-fold lower than those in castrate subjects (24.9 +/- 2.0 vs. 66.8 +/- 20.1 IU/liter; P < 0.005). From this human model of acute sex steroid withdrawal, we conclude that Inh B is likely to be the major feedback regulator of FSH secretion in the human male.

Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism.

Mutations in the GnRH receptor (GNRHR) have been described as a cause of reproductive failure in a subset of patients with idiopathic hypogonadotropic hypogonadism (IHH). Given the apparent rarity of these mutations, we set out to determine the frequency and distribution of GNRHR mutations in a heterogeneous population of patients with IHH who were well characterized with respect to diagnosis, phenotype, and mode of inheritance and to define their distribution within the receptor protein. One hundred and eight probands with IHH were screened for mutations in the coding sequence of GNRHR. Forty-eight of the 108 patients had a normal sense of smell, whereas the remaining 60 had anosmia or hyposmia (Kallmann syndrome). Exon segments in the GNRHR were screened for mutations using temperature gradient gel electrophoresis, and all mutations were confirmed by direct sequencing. Five unrelated probands (3 men and 2 women), all normosmic, were documented to have changes in the coding sequence of the GNRHR. Two of these probands were from a subgroup of 5 kindreds consistent with a recessive mode of inheritance, establishing a GNRHR mutation frequency of 2 of 5 (40%) in patients with normosmic, autosomal recessive IHH. The remaining 3 probands with GNRHR mutations were from a subgroup of 18 patients without evidence of familial involvement, indicating a prevalence of 3 of 18 (16.7%) in patients with sporadic IHH and a normal sense of smell. Among the five individuals bearing GNRHR mutations, a broad spectrum of phenotypes was noted, including testicular sizes in the male that varied from prepubertal to the normal adult male range. Three probands had compound heterozygous mutations, and two had homozygous mutations. Of the eight DNA sequence changes identified, four were novel: Thr(32)Ile, Cys(200)Tyr, Leu(266)Arg, and Cys(279)TYR: COS-7 cells transiently transfected with complementary DNAs encoding the human GNRHR containing each of these four novel mutations failed to respond to GnRH agonist stimulation. We conclude that 1) the spectrum of phenotypes in patients with GNRHR mutations is much broader than originally anticipated; 2) the frequency of GNRHR mutations may be more common than previously appreciated in familial cases of normosmic IHH and infrequent in sporadic cases; and 3) functional mutations of the GNRHR are distributed widely throughout the protein.

Inhibin B secretion in males with gonadotropin-releasing hormone (GnRH) deficiency before and during long-term GnRH replacement: relationship to spontaneous puberty, testicular volume, and prior treatment--a clinical research center study.

To evaluate the physiology of inhibin B in the human male, we measured serum concentrations in normal adult men and men with isolated GnRH deficiency before and during long-term replacement with pulsatile GnRH. At baseline, inhibin B levels in the GnRH-deficient men (n = 31) were significantly lower than normal controls (85 +/- 10 pg/mL vs. 239 +/- 14 pg/mL; P < .01) and correlated positively with pretreatment testicular volume (r = .80, P = .001) and a history of spontaneous puberty, suggesting additional maturational influences on the both testicular volume and inhibin B secretion. Pulsatile GnRH administration was associated with significant increases in inhibin B, with levels averaging 108 +/- 7 pg/mL when serum LH, FSH, and T concentrations had reached the normal adult male range (n = 22; P = .02 vs. baseline). Continued GnRH administration for at least an additional year was not associated with further increases in inhibin B concentrations. Throughout the course of long-term pulsatile GnRH replacement, serum FSH levels were negatively correlated with inhibin B concentrations (e.g. r = -.71, P < 0.01; n = 14 treated 12 months after normalization of T). Although inhibin B concentrations did not correlated with sperm density during therapy, rates of fertility were higher in patients with higher baseline levels (inhibin B > or = 60 pg/mL). Increases in serum concentrations of inhibin B occurring during GnRH replacement demonstrate the gonadotropin regulation of gonadal inhibin B secretion. However, the variation in baseline inhibin B levels before GnRH administration suggests an additional gonadotropin-independent level of modulation. The negative correlation between FSH and inhibin B secretion in GnRH-deficient men receiving long-term GnRH replacement is consistent with a putative role of inhibin B in the negative feedback regulation of FSH, although direct confirmation of this role requires further investigation.

Safety and Tolerance of Lactobacillus reuteri in Healthy Adult Male Subjects

Thirty healthy, male subjects (age 18 to 75 yrs) were used in a two-group, double-blinded, parallel design to evaluate the safety and tolerance of a potential probiotic organism, Lactobacillus reuteri. Subjects (15/treatment) consumed two gelatin capsules daily for 21 d that contained either a freeze dried L. reuteri preparation in a cryoprotectant, or a placebo (cryoprotectant). The concentration of L. reuteri was such that subjects consumed 1 × 1011 CFU per day. The study was 28 d in length with daily documentation of the presence of gastrointestinal symptoms (nausea, diarrhoea, cramping, distention, flatulence, vomiting, constipation, burping and reflux). In addition, serum chemistries, haematology, urinalysis, urinary indican excretion, and faecal microbiota (L. reuteri and total Lactobacillus spp. enumeration) were measured weekly (day 0, 7, 14, 21 and 28). A physical exam was given on day 0, 21, and 28. An additional faecal sample was obtained on day 77 for microbial enumeration. Subjects could consume their regular diets; however, alcohol was not allowed. Physical exam and urinalysis parameters were not clinically different between treatments. Supplemental L. reuteri reduced (P < 0.05) urinary indican excretion at day 7, but had no effect (P > 0.05) on subsequent urine collections. Although significant differences were observed for a few of the serum chemistry and haematology variables, all of the values remained within the expected normal range for healthy adult males. Subjects consuming supplemental L. reuteri had increased (P < 0.01) levels of L. reuteri in their faeces on day 7, 14, 21, and 28. However, colonisation was lost within 2 mths of termination of L. reuteri consumption (day 77). Levels of total Lactobacillus spp. never differed (P > 0.05) between treatments; however, the ratio of L. reuteri: total Lactobacillus spp. increased (P < 0.05) for subjects consuming supplemental L. reuteri. Incidence of subjective tolerance factors was infrequent and similar for both treatments. In conclusion, supplemental L. reuteri may be fed at 1 × 1011 CFU/day without any clinically significant safety or tolerance problems. Intake of L. reuteri (1 × 1011 CFU/day) results in colonisation (as measured by faecal level) within 7 d of consumption and is maintained for at least 7 d post consumption; however, colonisation is lost within 2 mths of washout.

Induction of spermatogenesis with gonadotrophins in Chinese men with hypogonadotrophic hypogonadism.

The effects of gonadotrophin administration to 17 Chinese patients with hypogonadotrophic hypogonadism (HH) on testicular volume and induction of spermatogenesis were studied. Ten subjects had isolated HH and seven had hypopituitarism. Twelve of the subjects had prepubertal onset of HH and five of them had been treated previously with hCG for induction of puberty. None had a history of cryptorchidism. During hCG treatment for induction of spermatogenesis, all subjects had an increase in serum levels of testosterone into the normal adult male range and their testes increased in size from 3 (1-20) ml to 11.6 (5-20) ml [median(range), p < 0.02]. Six subjects required treatment with hCG alone. However, the remaining 11 subjects, after at least 6 months treatment with hCG, required the addition of human menopausal gonadotrophin (hMG) to induce spermatogenesis. Two subjects remained azoospermic. One had a history of mumps orchitis and the other had isolated elevation of blood FSH levels, suggestive of primary testicular failure in addition to HH. Excluding one subject with fertile eunuch syndrome, the mean duration for first appearance of spermatozoa was 13 (4-52) months. Twelve subjects became fertile and pregnancy was achieved in their partners after 20 (4-78) months. The weekly doses for hCG and hMG were 4000 (3000-10,000) IU and 225 (225-450) IU, respectively. Patients who responded to hCG alone had a significantly larger pretreatment testicular volume, suggesting that they had only partial gonadotrophin deficiency. Prepubertal onset of hypogonadism was not a determining factor for requirement of hMG treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

NORMAL PUBERTY IN X-LINKED CYTOMEGALIC CONGENITAL ADRENAL HYPOPLASIA (CCAH)

X-linkcd cytomegalic congenital adrenal hypoplasia (CCAH) is regularly associated with hypogonadotropic hypogonadism.3.2 To our knowledge, we are reporting for the first time a boy with well documented X-linked CCAH and normal pubertal development. The patient's brother had died at 5 6/12 years of age from undiagnosed adrenal insufficiency of recent onset due to histologically confirmed CCAH. Our patient developed primary adrenal insufficiency at 6 6/12 years of age, and has been doing well ever since on physiological replacement doses of hydrocortisone and fludrocortisone. At the time of diagnosis, there were negative or normal results for adrenal and other endocrine autoantibodies, very-long-chain fatty acids, serum and urinary glycerol, serum triglycerides, CK, and urinary organic acids. At 15 6/12 years of age, audiomctry was also documented to be normal.3 Spontaneous onset of puberty was evidenced by testicular enlargement and appearance of pubic hair in his 1 1th and 14th years of life, respectively, and by a corresponding growth spun. At 15 8/12 years of age, he had an adult sized phallus, testicular volume of 20 ml, and pubic hair stage IV (Tanner). Serum FSH (4.8/7.2 U/l) and LH (4.9/20 U/l) before and 30′ after LHRH (60 μg/m2 i.v.), a LH night profile (3 peaks up to 7.6 U/l), and serum testosterone (493 ng/dt) were within the normal range for adult males. Although molecular genetic studies have so far failed to identify a deletion on the short arm of the X chromosome in our patient, this unique case of normal puberty in CCAH supports the suggestion2,4 that a separate gene locus for hypogonadotropic hypogonadism is located distal to the glycerol kinase and CCAH genes.

Increases in bone density during treatment of men with idiopathic hypogonadotropic hypogonadism.

To assess the effects of gonadal steroid replacement on bone density in men with osteoporosis due to severe hypogonadism, we measured cortical bone density in the distal radius by 125I photon absorptiometry and trabecular bone density in the lumbar spine by quantitative computed tomography in 21 men with isolated GnRH deficiency while serum testosterone levels were maintained in the normal adult male range for 12-31 months (mean +/- SE, 23.7 +/- 1.1). In men who initially had fused epiphyses (n = 15), cortical bone density increased from 0.71 +/- 0.02 to 0.74 +/- 0.01 g/cm2 (P less than 0.01), while trabecular bone density did not change (116 +/- 9 compared with 119 +/- 7 mg/cm3). In men who initially had open epiphyses (n = 6), cortical bone density increased from 0.62 +/- 0.01 to 0.70 +/- 0.03 g/cm2 (P less than 0.01), while trabecular bone density increased from 96 +/- 13 to 109 +/- 12 mg/cm3 (P less than 0.01). Cortical bone density increased 0.03 +/- 0.01 g/cm2 in men with fused epiphyses and 0.08 +/- 0.02 g/cm2 in men with open epiphyses (P less than 0.05). Despite these increases, neither cortical nor trabecular bone density returned to normal levels. Histomorphometric analyses of iliac crest bone biopsies demonstrated that most of the men had low turnover osteoporosis, although some men had normal to high turnover osteoporosis. We conclude that bone density increases during gonadal steroid replacement of GnRH-deficient men, particularly in men who are skeletally immature.

β-Endorphin/β-lipotropin release and gonadotropin secretion after acute exercise in physically conditioned males

beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) concentrations were measured in the basal state and after acute exercise for 15 min or until exhaustion in 6 physically conditioned male volunteers. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and prolactin were also measured in the basal state. In addition, the concentrations of the gonadotropins (LH and FSH) were determined after exercise and the gonadotropin response to gonadotropin releasing hormone was assessed before and after exercise. The data show that acute exercise stimulates the release of both beta-EP and beta-LPH which return to base-line levels within 60 min after exercise. This is in contrast to our previously described results in physically unconditioned male volunteers in whom only beta-LPH release was noted after exercise. Serum LH concentrations declined after exercise reaching nadir values between 60 to 150 min after exercise. As we previously reported in physically unconditioned male volunteers, serum FSH concentrations did not change with exercise and the gonadotropin response to LRH stimulation was uninfluenced by exercise. Serum testosterone and prolactin concentration were within the normal range for healthy adult males. We speculate that the difference in beta-EP release with exercise in physically conditioned and unconditioned males represents a difference in processing of the opioid precursor molecule (pro-opiomelanocortin, POMC) in the two groups.

Clinical evidence on the role of oestrogens in the development of the breasts

SynopsisGirls start their puberty including breast development around age 8. Though the best correlation found is that with oestradiol, most girls still have at the onset of breast development oestrogen levels in the normal range for adult males. Therefore, it seems that oestrogen receptor sensitivity plays an important role in breast development. An important insight into the hormonal interplay in breast development was obtained when comparing the effect of exogenous oestrogens in forty-five girls with four different aetiologies of oestrogen deficiency: gonadal dysgenesis (GD). 17-alpha hydroxylase deficiency (17-OHase def), isolated gonadotrophin deficiency (IGnD) and multiple pituitary hormone deficiencies (MPHD). None of the girls had any breast development in the absence of oestrogens. Treatment with oestrogen was given in an identical manner to all. In GD, in whom the hypothalamic-pituitary functions were normal, treatment led to full development of breasts in a relatively short period. In IGnD and MPHD, breast development was incomplete even after years of oestrogen treatment. The conspicuous difference of the hormonal status between GD and IGnD and MPHD is that the latter two groups lack gonadotrophins, while in GD and 17-OHase def. these hormones are pathologically elevated. Thus the gonadotrophins seem to play an important role in mammary gland development. In the girl with 17-OHase def., it was also found that cortisol is necessary for normal breast development. A girl with hyperprolactinaemia due to a microadenoma had delayed puberty including slow breast development. Upon bromocriptine treatment the prolactin fell, the oestrogens rose and puberty including breast development occurred. Patients with Laron-type dwarfism (isolated IGF-I deficiency) have been found to have normal breast development.

Transdermal testosterone therapy in the treatment of male hypogonadism.

Five hypogonadal men were treated with transdermal testosterone therapy, using a testosterone patch applied to the scrotal skin. Daily application of the patch, which contained 10 mg testosterone, produced an increase in serum testosterone concentrations from a pretreatment value of 45 +/- 12 (+/- SE; 1.5 +/- 0.4) to 436 +/- 80 ng/dL (15.1 +/- 2.8 nmol/L; P less than 0.001) after 4 weeks of treatment. Normal serum testosterone concentrations were achieved in all men after 6-8 weeks of therapy and were maintained during continued long term therapy for 9-12 months with a patch containing 15 mg testosterone. All men reported a subjective increase in libido and sexual function during therapy, and three men preferred it to testosterone injections. The serum testosterone and estradiol levels did not rise above the normal adult male range at any time during therapy. However, elevated serum dihydrotestosterone (DHT) concentrations occurred during treatment; the pretreatment DHT concentration was 95 +/- 3 ng/dL (3.3 +/- 0.1 nmol/L), and it increased to 228 +/- 40 ng/dL (7.8 +/- 1.4 nmol/L) after 4 weeks of treatment and remained elevated thereafter. The individual mean DHT to testosterone ratio increased from a pretreatment value of 0.2 (range, 0.1-0.3) to 0.6 (range, 0.4-0.7) after 2 weeks of therapy and remained high thereafter. Comparison of the serum DHT levels in patients during therapy with those in normal men who had similar testosterone concentrations [531 +/- 62 vs. 566 +/- 72 ng/dL (18.4 +/- 2.1 vs. 19.6 +/- 2.5 nmol/L); P greater than 0.05] revealed that the mean serum DHT concentration was significantly higher in the patients [315 +/- 69 vs. 87 +/- 6 ng/dL (10.8 +/- 2.4 vs. 2.9 +/- 0.2 nmol/L); P less than 0.001], as was the mean DHT to testosterone ratio [0.6 (range, 0.25- 1.1) vs. 0.16 (range, 0.09- 0.24); P less than 0.001]. The high serum DHT levels presumably were due to increased metabolism of testosterone to DHT by the 5 alpha-reductase in the scrotal skin. Serum 3 alpha-androstanediol glucuronide levels were not elevated in the patients. We conclude that transdermal testosterone therapy is an effective long term treatment for hypogonadism in men. It is, however, associated with high serum DHT levels, whose potential long term effects on the prostate and other tissues need to be investigated.

Differential control of luteinizing hormone and follicle-stimulating hormone secretion by luteinizing hormone-releasing hormone pulse frequency in man.

To test the hypothesis that the frequency of pulsatile LHRH stimulation can differentially control LH and FSH secretion in man, we administered low doses of LHRH in pulsatile fashion in several different regimens to men with idiopathic hypogonadotropic hypogonadism (IHH) and presumed endogenous LHRH deficiency. In study 1, four men with IHH received a constant amount of LHRH per day in three different frequencies. After an initial 7-day period of LHRH (5.0 micrograms every 2 h), the men received 2.5 micrograms every 1 h and 7.5 micrograms every 3 h, each for 4 days, in varying order. Frequent blood samples were obtained before LHRH administration and at the end of each regimen. Before LHRH administration, mean serum FSH and LH levels were low [28 +/- 3 (+/- SEM) and 6 +/- 2 ng/mL, respectively], and they increased into the normal adult male range during LHRH treatment. As the frequency of LHRH administration decreased from every 1 to 2 to 3 h, serum FSH levels progressively increased from 99 +/- 33 to 133 +/- 34 to 181 +/- 58 ng/mL (P less than 0.05). Serum LH levels (34 +/- 6, 33 +/- 6, and 34 +/- 5 ng/mL) were significantly higher than those before LHRH administration and did not differ significantly among the three regimens. Total serum testosterone (T), estradiol, and free T levels were increased by LHRH, but were not significantly different during the three regions of LHRH administration. In study 2, three men with IHH received the same amount of LHRH per dose, given in two different pulse frequencies; 2.5 micrograms LHRH were administered in frequencies of every 0.5 h and every 1.5 h, each for 4 days, in varying order. During the 0.5 h frequency, the mean serum FSH level was 42 +/- 13 ng/mL, and it rose to 80 +/- 19 ng/mL during the 1.5 h frequency (P less than 0.05). Corresponding mean serum LH levels were 25 +/- 5 and 27 +/- 4 ng/mL. Serum T and estradiol levels were not significantly different during the two LHRH regimens. We conclude that the frequency of LHRH stimulation can differentially control FSH and LH secretion by the human pituitary gland, and the pattern of hormonal stimulation may be a determinant of target organ response.

Acute effects of natural and synthetic cannabis compounds on prolactin levels in human males

Plasma prolactin levels were determined in 23 adult males prior to and following administration of Δ 9-tetrahydrocannabinol (THC) (17.5 mg orally), a synthetic cannabis compound, Nabilone (2 mg orally), a 1-g marihuana cigarette containing 1.83% THC, smoked under controlled conditions and placebo capsules and cigarettes for each of the active cannabis compounds. In order to control for possible influence of previous cannabis use history on prolactin response, three groups of subjects were studied— regular (daily) marihuana users, intermittent (weekly) marihuana users, and occasional (monthly) marihuana users. Each subject served as his own control for each drug condition. Double blind studies were conducted on a residential research ward. All baseline prolactin values were within the normal range for healthy adult males. There were no statistically significant differences in plasma prolactin levels among the three subject groups prior to administration of THC, Nabilone, marihuana or their respective placebos. There were no statistically significant changes in prolactin levels following TCH, Nabilone or marihuana smoking. Only placebo administration to regular and occasional marihuana users was followed by a significant increase in plasma prolactin levels. These findings indicate that acute administration of cannabis compounds, either orally or via smoking, does not significantly affect plasma prolactin levels in adult human males.

Postmortem plasma luteinizing hormone levels and antemortem violence

Luteinizing hormone (LH) levels were determined in postmortem blood samples obtained from twenty-eight men who sustained sudden traumatic deaths. Violent antemorten behavior (committing suicide by gunshot or hanging, or killed during a violent attack or physical struggle) was associated with significantly higher LH levels than nonviolent antemortem behavior (pedestrians struck by vehicles, crime victims, and those shot during verbal arguments). Within both the violent and nonviolent groups, LH levels were higher in men with detectable alcohol in blood than in men with no alcohol in blood but these differences were not statistically significant. In the nonviolent group, men without alcohol in blood had LH levels within the normal range for healthy adult males. The stability of LH was established in serial studies of normal human male blood specimens over a range of temperatures and time durations comparable to conditions in postmortem blood sampling procedures. These findings suggest that postmortem LH levels in males may be a biological indicator of violent behavior immediately preceding death.

Male pseudohermaphroditism due to 17 β-hydroxy steroid dehydrogenase deficiency

SummaryA case of male pseudohermaphroditism (46XY) due to 17β-hydroxysteroid dehydrogenase deficiency in a 14-year-old child is reported. The patient, unambiguously brought up as a girl, had noted clitoromegaly 10 months before presentation, together with deepening of voice, facial acne and absence of breast development or menstruation. Inguinal testes were palpable. Serum androstenedione was greatly elevated, whereas testosterone and dihydrotestosterone were at the lower end of the normal adult male range; serum oestradiol, oestrone and gonadotrophins were elevated. Testicular biopsy showed pronounced hyperplasia of the Leydig cells and absence of spermatogenesis. Incubation of slices of testicular tissue with 17α-hydroxyprogesterone showed no significant conversion of androstenedione to testosterone, yet abundant androgen receptor activity was demonstrated