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D J Handelsman

Publications and source records attributed to D J Handelsman.

At least 37 records · Page 2Linked to original sources
PubMed2001

First human exposure to FSH-CTP in hypogonadotrophic hypogonadal males.

BACKGROUND: This is the first report of human exposure to the novel compound follicle stimulating hormone (FSH)-C-terminal peptide (CTP) 'FSH-CTP' (Org 36286), a long-acting recombinant FSH like substance, consisting of the alpha-subunit of human FSH and a hybrid beta-subunit. The latter is composed of the beta-subunit of human FSH and the C-terminus part (CTP) of the beta-subunit of human chorionic gonadotrophin (HCG). METHODS: In this phase I, non-blind, multi-centre study, 13 hypogonadotrophic hypogonadal male subjects were enrolled to test the safety of FSH-CTP in terms of antibody formation in humans. Furthermore, the pharmacokinetic profile of this new compound was determined. Subjects were injected four times with 15 microg FSH-CTP with an interval of approximately 4 weeks between each injection. RESULTS: No drug related (serious) adverse events occurred. No antibodies against FSH-CTP or chinese hamster ovary (CHO)-cell derived proteins were detected and measurement of local tolerance demonstrated that s.c. administration of FSH-CTP is well tolerated and no increase in intensity of injection-site responses was observed after repeated exposure to FSH-CTP. After the first and third injection, FSH-CTP serum concentrations were determined. Overall mean (+/- SD) C(max) was 0.426 (+/- 0.116) ng/ml, mean t(1/2) and AUC(0-infinity) were 94.7 (+/- 26.2) h and 81.5 (+/- 18.8) ng.h/ml respectively. Compared with recFSH (Puregon), the half life of FSH-CTP was increased 2-3 times. Following the first and third injection a clear rise in serum inhibin-B concentrations were observed. CONCLUSIONS: The use of FSH-CTP is safe and does not lead to detectable formation of antibodies. Furthermore, the pharmacokinetic and dynamic profile of FSH-CTP may lead to the development of new, more convenient regimens for the treatment of male and female infertility.

Adult↗
PubMed2001

A novel transgenic model to characterize the specific effects of follicle-stimulating hormone on gonadal physiology in the absence of luteinizing hormone actions.

Gonadal function is wholly reliant on the two pituitary-derived gonadotropins, FSH and LH. Identifying the specific effects of FSH has been difficult because of the intimate relationship between LH and FSH action and inherent limitations of classic research paradigms. We describe a novel transgenic model to characterize the definitive actions of FSH alone, distinct from LH effects, created by combining transgenic FSH expression with the gonadotropin-deficient background of the hypogonadal (hpg) mouse. A tandem transgene construct encoding each alpha- and beta-subunit of human FSH, under the rat insulin II promoter, expressed biologically active heterodimers at serum levels, by immunoassay, equivalent to circulating FSH concentrations in fertile humans (0.1-25 IU/liter). Transgenic mice were crossed into the hpg mouse genotype to obtain LH-deficient animals secreting FSH alone. Testis weights of adult FSHxhpg mice were increased up to 5-fold, relative to nontransgenic hpg controls (P < 0.001). However, only transgenic males with serum FSH levels more than 1 IU/liter showed testis weights increased relative to hpg controls, indicating a physiological FSH threshold for the testicular response. Histology of enlarged FSHxhpg testes revealed round spermatids and sparse numbers of elongated spermatids, demonstrating that the testosterone-independent FSH response targeting the Sertoli cell can facilitate completion of meiosis and minimal initiation, but not completion, of spermiogenesis. Transgenic FSH also induced inhibin B secretion in FSHxhpg mice, but showed a distinct sexual dimorphism with only females exhibiting a strong FSH dose-dependent increase in serum inhibin B levels (r(2) = 0.84). In addition, ovaries of FSHxhpg females were enlarged up to 10-fold (P < 0.001), characterized by increased follicular recruitment and development to type 7 antral follicles. Thus, these findings show that the transgenic FSHxhpg mouse provides a unique model for detailed investigations of the definitive in vivo actions of FSH alone.

Animals↗
PubMed2001

Pharmacogenetic polymorphisms of the AR and metabolism and susceptibility to hormone-induced azoospermia.

Clinical trials of hormonal male contraceptive regimens have identified a consistent population polymorphism in susceptibility to hormone-induced azoospermia. Using identical hormonal regimens, fewer men of European origin (approximately two thirds) become azoospermic compared with Asian men who virtually all become azoospermic. This variation within and between populations remains unexplained. To investigate pharmacogenetic differences in androgen metabolism or action that might explain variable susceptibility to hormonal-induced azoospermia, we studied single nucleotide polymorphism in the CYP3A4 gene, which encodes the major hepatic T-inactivating enzyme, and CAG and GGC triplet repeats in the AR gene in 75 Australian volunteers participating in a male hormonal contraceptive study and 106 population controls. These men were classified into groups according to whether 6 months of weekly T enanthate injections produced azoospermia (n = 54), near-azoospermia (n = 7), and nonazoospermia (n = 14). Mutagenically differentiated PCR was designed to identify A/G variants in the promoter region of the CYP3A4 gene. Fluorescent-labeled DNA fragments containing either CAG or GGC repeats were amplified from the genomic DNA, and their sizes were determined based on the capillary electrophoresis. The G allele of CYP3A4 gene was absent from the nonazoospermia and near-azoospermia groups, but overall this single nucleotide polymorphism distribution did not differ significantly between men in the azoospermia group or population controls. There were no significant differences in distribution of CAG and GGC triplet repeats among three groups or between them and the population controls based on the maximum likelihood estimate of the odds ratio and CLUMP II analyses. These results suggested that neither genetic polymorphisms in the AR gene (CAG and GGC repeats) nor that in hepatic androgen metabolism (CYP3A4 A/G variant) were the major contributors to the within-population variations in susceptibility to T-induced azoospermia.

Adult↗
PubMed2001

A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency.

The efficacy and safety of androgen supplementation in older men remains controversial. Despite biochemical evidence of partial androgen deficiency in older men, controlled studies using T demonstrate equivocal benefits. Furthermore, the importance of aromatization and 5alpha reduction in androgen actions among older men remains unclear. Dihydrotestosterone is the highest potency natural androgen with the additional features that it is neither aromatizable nor susceptible to potency amplification by 5alpha reduction. Therefore, the effects of dihydrotestosterone may differ from those of T in older men. This study evaluated the efficacy and safety of 3 months treatment with transdermal dihydrotestosterone gel on muscle strength, mobility, and quality of life in ambulant, community-dwelling men aged 60 yr or older. Eligible men (plasma T < or =15 nmol/liter) were randomized to undergo daily dermal application of 70 mg dihydrotestosterone gel (n = 18) or vehicle (n = 19) and were studied before, monthly during, and 1 month after treatment. Among 33 (17 dihydrotestosterone, 16 placebo) men completing the study with a high degree of compliance, dihydrotestosterone had significant effects on circulating hormones (increased dihydrotestosterone; decreased total and free testosterone, LH, and FSH; unchanged SHBG and estradiol), lipid profiles (decreased total and low-density lipoprotein cholesterols; unchanged high-density lipoprotein cholesterol and triglycerides), hematopoiesis (increased hemoglobin, hematocrit, and red cell counts), and body composition (decreased skinfold thickness and fat mass; unchanged lean mass and waist to hip ratio). Muscle strength measured by isokinetic peak torque was increased in flexion of the dominant knee but not in knee extension or shoulder contraction, nor was there any significant change in gait, balance, or mobility tests, in cognitive function, or in quality of life scales. Dihydrotestosterone treatment had no adverse effects on prostate (unchanged prostate volumes and prostate-specific antigen) and cardiovascular (no adverse change in vascular reactivity or lipids) safety markers. We conclude that 3 months treatment with transdermal dihydrotestosterone gel demonstrates expected androgenic effects, short-term safety, and limited improvement in lower limb muscle strength but no change in physical functioning or cognitive function.

Administration, Cutaneous↗
PubMed2001

Quantitative reverse transcriptase polymerase chain reaction assay for mouse androgen receptor mRNA.

A quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay for mouse androgen receptor (AR) mRNA was developed to study relative changes in AR gene expression. Serial dilutions of a standard comprising a fragment of the ampicillin resistance gene flanked by the primer sequences of the AR mRNA were added to a constant amount of total RNA for RT-PCR. Primers were designed to generate a 541-bp fragment of mouse AR mRNA (target [T]) and a 460-bp fragment of the standard (S). PCR products were resolved by gel electrophoresis and quantitated by densitometry. A standard curve was generated for each sample by plotting the logarithm of T/S products vs the logarithm of the amount of S added. The amount of T was determined from the standard curve where intensities of PCR products of T and S were equal. The assay was validated by measuring the relative abundance of AR mRNA in 10 mouse tissues, and results were consistent with studies of AR expression in rat tissues. Assay reproducibility, tested by repeating assays on four different tissues on different days from the RT step, had a coefficient of variation of 6-16%. The current assay is thus both reproducible and valid in quantitation of mouse AR mRNA.

Adrenal Glands↗
PubMed2000

Use, misuse and abuse of androgens. The Endocrine Society of Australia consensus guidelines for androgen prescribing.

Androgen replacement therapy (ART) is usually life-long, and should only be started after androgen deficiency has been proven by hormone assays. The therapeutic goal is to maintain physiological testosterone levels. Testosterone rather than synthetic androgens should be used. Oral 17 alpha-alkylated androgens are hepatotoxic and should not be used for ART. There is no indication for androgen therapy in male infertility. Although androgen deficiency is an uncommon cause of erectile dysfunction, all men presenting with erectile dysfunction should be evaluated for androgen deficiency. If androgen deficiency is confirmed, investigation for the underlying pathological cause is required. Contraindications to androgen therapy are prostate and breast cancer. Precautions include using lower starting doses for older men and induction of puberty. Intramuscular injections should be avoided in men with bleeding disorders. Androgen-sensitive epilepsy, migraine, sleep apnoea, polycythaemia or fluid overload need to be considered. Competitive athletes should be warned about the risks of disqualification. ART should be initiated with intramuscular injections of testosterone esters, 250 mg every two weeks [corrected]. Maintenance requires tailoring treatment modality to the patient's convenience. Modalities currently available include testosterone injections, implants, or capsules. Choice depends on convenience, cost, availability and familiarity. There is no convincing evidence that, in the absence of proven androgen deficiency, androgen therapy is effective and safe for older men per se, in men with chronic non-gonadal disease, or for treatment of non-specific symptoms. Until further evidence is available, such treatment cannot be recommended.

Anabolic Agents↗
PubMed2000

Androgen receptor expression is greater in macrophages from male than from female donors. A sex difference with implications for atherogenesis.

BACKGROUND: Male sex is an independent risk factor for the extent and severity of atherosclerosis. The influence of androgens on foam cell formation, a key event in atherogenesis, has not yet been investigated. METHODS AND RESULTS: Primary human monocytes were allowed to differentiate into macrophages. RNA was then extracted from healthy male-donor (n=8) and premenopausal female-donor (n=8) macrophages, and message for the androgen receptor (AR) was examined by RT-PCR. There was a significantly higher level of AR mRNA in macrophages isolated from men than in those from women (0.64+/-0.06 versus 0.15+/-0.02 amol/microgram total RNA; P<0.001). AR mRNA levels were similar in macrophages from postmenopausal and premenopausal women (P=0.16). The functional consequence of this sex difference was then explored. Lipid-loading studies were performed on male (n=9) macrophages treated with the androgen dihydrotestosterone (DHT) and/or the AR antagonist hydroxyflutamide. These showed that DHT caused a dose-dependent and receptor-mediated increase in macrophage cholesteryl ester content (109+/-10%, 117+/-3%, and 120+/-4% for 4, 40, and 400 nmol/L DHT, respectively, as a percentage of control, P=0.002; 95+/-8% for DHT with hydroxyflutamide, P=0.58 versus controls). By contrast, there was no significant effect of androgen on lipid loading in female-donor macrophages (P>0.2 versus controls). CONCLUSIONS: Sex differences in androgen-mediated macrophage lipid loading may contribute to the greater prevalence and severity of atherosclerosis in men.

Adult↗
PubMed2000

Oestradiol enhances testosterone-induced suppression of human spermatogenesis.

The aim of this study was to determine for the first time in humans, the efficacy of adding a low dose oestradiol to a suboptimally suppressive testosterone dose in a depot hormonal regimen to suppress spermatogenesis in healthy eugonadal men. Twenty-six healthy men were randomized into groups that were treated by a single subdermal implantation of either 600 mg testosterone alone (T; n = 11) or together with 10 mg (TE10, n = 7) or 20 mg (TE20, n = 8) oestradiol. Administration of oestradiol produced a dose-dependent increase in peak plasma oestradiol at 1 month and prolonged suppression of plasma LH and FSH leading to significantly enhanced suppression of sperm output. Despite the augmented spermatogenic suppression, there was no significant difference in the proportions achieving azoospermia (6/26, 23%) or severe oligozoospermia (<1 or <3 x 10(6) spermatozoa per ml, 7/26, 27%) and overall these proportions were inadequate to provide reliable contraception according to the standards identified in World Health Organization male contraceptive efficacy studies. Total and free testosterone remained within the eugonadal reference range for young men throughout the study. While the lower oestradiol dosage had minimal spermatogenic suppression effects, the higher dose produced dose-limiting adverse effects of androgen deficiency and/or oestrogen excess between the fourth and sixth month of the study. This appeared to be due to the unexpectedly prolonged, low concentration of oestradiol release from the oestradiol implants. There were no significant treatment-related changes in body composition, lipids, prostate-specific antigen, haematological or biochemical variables. Thus oestradiol has a low therapeutic window and dose-limiting side-effects at dosages that fail to achieve the uniform azoospermia required of an effective male hormonal contraceptive regimen.

Adolescent↗
PubMed2000

Quality of nucleic acids extracted from fresh prostatic tissue obtained from TURP procedures.

PURPOSE: The molecular genetic study of benign prostatic hyperplasia (BPH) requires high quality nucleic acids from BPH tissue. It has been generally assumed, but not experimentally proven, that the diathermy used in trans-urethral resection of the prostate (TURP) damages nucleic acids. MATERIALS AND METHODS: Total RNA, polyA+ RNA and genomic DNA isolated from fresh tissue obtained from TURP procedures were compared with those isolated from tissue obtained from open prostatectomy. RESULTS: On a formaldehyde agarose gel, there was an increase in low molecular weight RNA in the TURP derived samples, in comparison to that in the open prostatectomy derived samples. The 28S and 18S rRNA were present in all TURP specimens and although the two bands were reduced in some samples, there were samples in which the 2 bands were indistinguishable from the open prostatectomy derived samples. Low molecular weight fragments seen in total RNA were reduced greatly in polyA+ RNA and the difference in polyA+ RNA between the TURP and open prostatectomy derived samples was significantly diminished. RT-PCR of two ubiquitously expressed gene transcripts (Galpha11, 256 bp and HPRT, 847 bp) yielded products of similar size and intensity between TURP and open prostatectomy derived samples. Genomic DNA obtained from TURP derived specimens showed no difference in size or enzyme digestibility in comparison to that from open prostatectomy. CONCLUSIONS: Nucleic acids extracted from fresh prostatic tissue derived from TURP procedures can be used as readily as any other fresh tissue for RT-PCR based molecular genetic studies, although polyA+ RNA isolation is recommended if degradation-free RNA is required.

DNA↗
PubMed1999

Androgen exposure increases human monocyte adhesion to vascular endothelium and endothelial cell expression of vascular cell adhesion molecule-1.

BACKGROUND: Male sex is an independent risk factor for coronary artery disease. Owing to the importance of monocyte adhesion to endothelial cells in the development of atherosclerosis, we hypothesized that androgens might promote this process. We therefore studied the effects of the nonaromatizable androgen dihydrotestosterone (DHT) on human monocyte adhesion to human endothelial cells and on endothelial cell-surface expression of adhesion molecules. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) were grown to confluence in media supplemented with postmenopausal female serum, then exposed for 48 hours to either DHT (40 and 400 nmol/L), with or without the androgen receptor blocker hydroxyflutamide (HF) (4 micromol/L); HF alone; or vehicle control (ethanol 0.1%). Human monocytes obtained by elutriation were incubated for 1 hour with the HUVECs at 37 degrees C, and adhesion was measured by light microscopy. Compared with vehicle control, monocyte adhesion was increased in the androgen-treated HUVECs in a dose-dependent manner (116+/-6% and 128+/-3% for DHT 40 and 400 nmol/L respectively; P<0.001). HF blocked this increase (P>/=0.3 compared with control). Surface expression of endothelial cell adhesion molecules was measured by ELISA and revealed an increased expression of vascular cell adhesion molecule-1 (VCAM-1) in the DHT-treated HUVECs (125+/-5% versus 100+/-4% in controls; P=0.002), an effect also antagonized by HF (P>/=0.3 compared with controls). Furthermore, the DHT-related increase in adhesion was completely blocked by coincubation with anti-VCAM-1 antibody. Comparable results were obtained in arterial endothelial cells and in endothelium stimulated with the cytokine tumor necrosis factor-alpha. CONCLUSIONS: Androgen exposure is associated with increased human monocyte adhesion to endothelial cells, a proatherogenic effect mediated at least in part by an increased endothelial cell-surface expression of VCAM-1.

Antibodies, Monoclonal↗
PubMed1999

Adrenal and gonadal contributions to urinary excretion and plasma concentration of epitestosterone in men--effect of adrenal stimulation and implications for detection of testosterone abuse.

OBJECTIVE: The ratio of urinary testosterone (T) to epitestosterone (EpiT) is used to detect T abuse in sport. Also, plasma or urinary concentrations of EpiT have been measured to assess testicular steroidogenesis during hormonal male contraception. Further investigations are required to evaluate the relative contributions of the testis and adrenal to EpiT production. To this purpose, we have compared basal urinary EpiT glucuronide and plasma EpiT and the response to synthetic adrenocorticotrophic hormone (ACTH) stimulation between eugonadal and hypogonadal men. DESIGN AND SUBJECTS: The basal urinary excretion rate of EpiT glucuronide was determined in 34 eugonadal men. Six men, clinically diagnosed as hypogonadal, and 6 out of the 34 eugonadal men previously described, received an intramuscular injection of synthetic ACTH depot (1 mg) at 0800 h on two consecutive days. Blood samples were collected prior to and then at 1.5, 8, 24, 25.5, 32 and 48 h with respect to the first administration (0 h). 24-h urine specimens were collected from 0800 h on days 1 and 2 (baseline) and 3 and 4 (stimulation). MEASUREMENTS: Plasma EpiT, T and cortisol were measured by RIA and urinary EpiT and T, following glucuronide hydrolysis, by gas chromatography-mass spectrometry (extract combines aglycones with a minor amount of urinary free steroids). RESULTS: Basal excretion rates of EpiT glucuronide in eugonadal men (range: 62-751 nmol/24 h) were considerably greater than in hypogonadal men (range: 3-34 nmol/24 h). Mean basal plasma EpiT in eugonadal men (1.32 +/- 0.08 nmol/l) were greater than in hypogonadal men (0.68 +/- 0.04 nmol/l). In each group, synthetic ACTH stimulation increased plasma cortisol 4-fold. In eugonadal men, plasma and urinary EpiT were unchanged whereas plasma and urinary T glucuronide decreased in response to ACTH. In hypogonadal patients, ACTH increased plasma and urinary EpiT while plasma T remained unchanged. CONCLUSION: The testes are the major source of epitestosterone, the adrenal contribution being relatively modest. Following adrenal stimulation, urinary epitestosterone glucuronide increases considerably in hypogonadal men but this increase is masked in eugonadal men because testicular production is probably suppressed by the ACTH-induced rise in cortisol. Activation of the adrenal cortex results in no change or only a small decrease in the urinary T/EpiT ratio in eugonadal men.

Adrenal Glands↗
PubMed1999

Extrusion of testosterone pellets: a randomized controlled clinical study.

BACKGROUND: It has previously been shown that testosterone implantation is an effective and well accepted form of androgen replacement therapy, but that pellet extrusion was the most frequent side-effect. The present study aimed to reduce the extrusion rate. OBJECTIVE: To determine whether the washing of testosterone pellets to remove potentially surface-adherent particles decreased the rate of extrusion of pellet implants. DESIGN: Prospective, randomized parallel group design in a single centre with consecutive procedures to be randomized (1 : 1) into a wash or control group. PATIENTS: The study included 251 testosterone implantation procedures in men with known androgen deficiency. MEASUREMENTS: The primary endpoint, extrusion rate per procedure, was evaluated prospectively by telephone contact at 1 week and then 3 and 6 month intervals. Secondary end-points included peri-procedure adverse events (bleeding, skin reaction, excessive discomfort) noted at the time of implant. Bruising, bleeding and infection were also evaluated as later adverse events by telephone and personal follow-up. Explanatory variables recorded as possible covariables included the number of implants used, production batch number of the implants, the operator, as well as other demographic and medical factors. RESULTS: In the wash group, the extrusion rate was 12% per procedure (19 pellets from 15 subjects) whereas in the control group, the extrusion rate was 11.1% per procedure (18 pellets from 14 subjects), indicating no evidence of any benefit of the wash procedure (OR = 1. 09 [95% CI 0.47-2.6] per procedure). There was no evidence of benefit in secondary endpoints including total adverse events (7.1%, OR 1.28 [0.44-3.9], bleeding/bruising (8.8%, 1.23 [0.47-3.3]) and infection (4.0%, 1.54 [0.35-7.6]) per procedure. Among men reporting an infection requiring antibiotic treatment according to their own general practitioners, six/ten (60%) subsequently experienced an extrusion. There were no significant differences in extrusion rate between four different operators (P = 0.24) nor among 12 different batches of pellets used during the course of the study (P = 0.77). CONCLUSIONS: The pellet washing procedure used during implantation does not reduce the subsequent extrusion rate. The higher rate of both primary and secondary adverse events in this prospective study compared with the previous retrospective survey may reflect either more rigorous follow-up or a secular trend.

Drug Implants↗
PubMed1999

Efficacy and safety of recombinant human follicle stimulating hormone (Gonal-F) with urinary human chorionic gonadotrophin for induction of spermatogenesis and fertility in gonadotrophin-deficient men.

In order to evaluate the efficacy and safety of recombinant human follicle stimulating hormone (r-hFSH) in combination with urinary human chorionic gonadotrophin (HCG) to induce spermatogenesis and fertility in gonadotrophin-deficient men, we conducted a prospective, open, non-comparative multicentre study in two Australian academic medical centres. Ten men with gonadotrophin deficiency requiring induction of spermatogenesis and fertility were treated with HCG for 3-6 months followed by the s.c. self-administration of injections of r-hFSH in combination with HCG for 18 months. Among the eight men who commenced r-hFSH treatment, seven demonstrated sperm output at a median of 6 months and five achieved the target sperm output of 1. 5x10(6) per ml at a median of 9 months of FSH treatment. Mean testicular volume increased by 4.2 ml during FSH treatment. Three men produced pregnancies in their partners, two of which resulted in the birth of healthy babies and a third patient's partner had a miscarriage. We conclude that r-hFSH is well tolerated and effective in inducing testis growth, spermatogenesis and fertility in gonadotrophin-deficient men. The efficacy of r-hFSH seems comparable with urinary FSH at restoring normal fertility in gonadotrophin-deficient men.

Adolescent↗
PubMed1999

Imprinting by neonatal sex steroids on the structure and function of the mature mouse prostate.

Perinatal sex-steroid exposure may result in permanent modifications in the structure and function of the prostate gland. The mechanism of such long-range alterations in hormonal sensitivity is not known. This study aimed to define the molecular requirements for neonatal sex-steroid imprinting and to investigate whether combined administration of neonatal androgens and estrogens had synergistic effects upon the mature mouse prostate. Since the interaction between endogenous and exogenous sex steroids in normal mice makes it difficult to dissociate direct from indirect effects, we used the hypogonadal (hpg) mouse, characterized by congenital androgen deficiency yet still fully responsive to exogenous androgens. Newborn mice (Days 1-2) were administered a single s.c. injection of androgens alone or in combination with an estrogen followed by testosterone-induced maximal prostate growth at maturity. The final effects were determined in 7-wk-old mice through study of ductal architecture in microdissected ventral prostates (VP) and quantitation of volume densities and diameters of prostate tissue components. A single neonatal dose of androgens, but not of estrogen, increased branching morphogenesis and VP weights at adulthood. These effects did not differ significantly between various androgens; in addition, combined androgen and estrogen treatment failed to demonstrate any synergistic effects on the prostate. We conclude that neonatal androgens induce long-range effects upon the mature VP structure as well as its secretory function and that this imprinting occurs via the androgen receptor without requiring aromatization of androgens. However, these conclusions, based on a specific treatment protocol, are confined only to the distal segment of VP, and effects of neonatal sex-steroid exposure in other regions or lobes of VP may differ.

Androgens↗
PubMed1999

Spermatogenesis without gonadotropins: maintenance has a lower testosterone threshold than initiation.

We showed previously that testosterone (T) alone could induce spermatogenesis and produce normally fertile spermatozoa in the absence of circulating gonadotropins. These studies used the hpg mouse, which is characterized by a congenital gonadotrophin deficiency due to a major deletion in the GnRH gene. Administering T by a subdermal implant of a SILASTIC brand tube impregnated with crystalline T showed that the androgenic requirement for full induction of spermatogenesis was a 1-cm length implant. Using this unique model of spermatogenesis without gonadotropins, we have now investigated the quantitative requirement for androgens to maintain spermatogenesis by testing the hypothesis that the androgenic threshold required for induction and maintenance of spermatogenesis are the same. Spermatogenesis was induced in homozygous hpg mice by T administration for 6 weeks. The first experiment determined the time-course of the regression of spermatogenesis after removal of the T-impregnated SILASTIC brand implant. Elongated spermatids were absent by 3 weeks and testicular weight regression was maximal by 4 weeks after androgen withdrawal. The second experiment examined the effects on maintenance of spermatogenesis of reducing the T dose. After full induction of spermatogenesis in homozygous hpg mice, the T implants were replaced with a range of smaller size T-impregnated SILASTIC brand implants for a further 4 weeks. All androgen-sensitive end-points (testis weight, tubular, and luminal diameters, round spermatids) were fully maintained with T implants of 0.06 cm and elongated spermatids with T implants of 0.25 cm. A further experiment showed that at very low T doses (0.06, 0.125 cm) the T effects observed at 4 weeks were maintained at 6 and 11 weeks duration. We conclude that the androgenic threshold to maintain spermatogenesis in the mouse is an order of magnitude lower than the threshold required for inducing spermatogenesis. This distinction suggests that the mechanism of action of testosterone in inducing spermatogenesis may involve regulation of a genetic switch to complete meiosis, whereas the maintenance involves a different locus of action. These findings suggest that further studies of androgen-dependent meiotic genes may be central to understanding the regulation and molecular basis of androgen-driven induction and maintenance of spermatogenesis.

Androgens↗