C. Alvin Paulsen

Data from men in greater Seattle area reveals no downward trend in semen quality : further evidence that deterioration of semen quality is not geographically uniform

Objective To determine whether there has been a decline in semen quality in a group of healthy men during the past 21 years. Design Retrospective analysis of the relationship between time and changes in semen parameters over 21 years using regression analysis. Setting A tertiary university center. Patients Five hundred ten healthy, normal men who donated multiple semen samples as participants in clinical studies between 1972 and 1993. Main Outcome Measures Sperm concentration, semen volume, total numbers of sperm per ejaculate, and percent spermatozoa with normal morphology. Results There was no decrease in sperm concentration, semen volume, total number of sperm per ejaculate, and percent normal sperm morphology in 510 healthy men studied between 1972 and 1993. Conclusion We conclude that in this population of healthy young men there has not been any decline in semen quality in the past 21 years.

Klinefelter syndrome: Expanding the phenotype and identifying new research directions

Purpose The purpose of this study is to summarize new data on etiology and clinical features of Klinefelter syndrome in order to derive research priorities.Methods This study was conducted using critical reviews of selective topics, emphasizing less well-recognized clinical findings.Results And Conclusions The phenotype of the prototypic 47,XXY case is well recognized: seminiferous tubule dysgenesis and androgen deficiency. Less well appreciated is the varied expressivity of 47,XXY Klinefelter syndrome, in particular neurological/cognitive perturbations like language and behavioral problems. Effective therapies are available. Reproductive technologies allow 47,XXY men to sire offspring through intracytoplasmic sperm injection (ICSI); however, genetic counseling is complex and success is low. Behavioral and expressive language difficulties are amenable to treatment by androgen therapy and psychological help. Early treatment may be imperative for optimal outcome.

Improvement in spermatogenesis following depression of the human testis with testosterone.

The short- and long-term effects of testosterone were studied in healthy young adult men. 13 patients were injected with 25 mg/day testosterone propionate for 24-29 days and 7 patients were implanted subcutaneously with 3-7 pellets (75 mg each) of unconjugated testosterone. Biopsies taken on the last day of injection and at 3 6 and 12 months after implantation revealed damage to both spermatogenesis and the interstitial Leydig cells. Most of the testicular changes were attributable to the withdrawal of gonadotropic stimulation. Some recovery of germinal and interstitial elements was observed in biopsies obtained 5-6 months after cessation of treatment. Biopsies taken 12-31 months after the termination of treatment indicated a marked improvement in testicular morphology and function compared to pre-treatment status. Disappearance of hyalinization of the seminiferous tubules was the most striking histological finding. Application of the rebound response to testosterone in the treatment of male infertility is discussed.

Follicle-stimulating Hormone and Human Spermatogenesis

The role of follicle-stimulating hormone (FSH) in the control of spermatogenesis is not well established in any species, including man. We studied the effect of an experimentally-induced, selective FSH deficiency on sperm production in normal men. After a 3-mo control period, five normal men received testosterone enanthate (T) 200 mg i. m. weekly to suppress luteinizing hormone (LH) and FSH, until three successive sperm counts revealed azoospermia or severe oligospermia (sperm counts <3 million/ml). Then, while continuing T, human chorionic gonadotropin (hCG) 5,000 IU i. m. three times weekly was administered simultaneously to replace LH activity, leaving FSH activity suppressed. The effect of the selective FSH deficiency produced by hCG plus T administration on sperm production was determined. Sperm counts (performed twice monthly throughout the study) were markedly suppressed during T administration alone (1.0+/-1.0 million/ml mean+/-SE, compared with 106+/-28 million/ml during the control period, P < 0.001). With the addition of hCG to T, sperm counts returned toward normal (46+/-16 million/ml, P < 0.001 compared with T alone). In two subjects, sperm counts during hCG plus T returned into the individuals control range. Sperm motility and morphology were consistently normal in all men during hCG plus T. Serum FSH levels by RIA were normal (110+/-10 ng/ml) in the control period and were suppressed to undetectable levels (<25 ng/ml) in the T alone and hCG plus T periods. Urinary FSH excretion was markedly suppressed in the T alone (60+/-15 mIU/h-2nd IRP, P < 0.01) and hCG plus T (37+/-9 mIU/h, P < 0.01) periods compared with the control period (334+/-78 mIU/h). We conclude that spermatogenesis as assessed by sperm counts, motilities, and morphologies may be reinitiated and maintained at normal levels in men with undetectable blood FSH levels and urinary excretion of FSH less than that of prepubertal children. This conclusion implies that, although FSH may exert effects on human testicular function, maintenance of normal spermatogenesis and reinitiation of sperm production after short-term suppression by exogenous steroids can occur in spite of nearly absent FSH stimulation.

Suppression of spermatogenesis and chronic toxicity in men by a new series of bis(dichloroacetyl) diamines

Three bis(dichloroacetyl) diamine compounds (Win 13,099, Win 17,416, Win, 18,446) have been studied for their effects on testicular physiology in human volunteers. These studies show that: 1. 1. Win 13,099, Win 17,416, and Win 18,446 do not inhibit the human pituitary and do not suppress Leydig-cell activity. 2. 2. Each of these compounds suppresses sperm output and motility and alters sperm morphology, as demonstrated by seminal fluid analyses. Histologic study of testicular biopsy specimens reveals suppression of spermatogenesis. The suppressive action of Win 17,416 is, perhaps, incomplete. Win 13,099 and Win 18,446 each reduce the sperm counts to below 4 million per cubic centimeter within 8–11 weeks. There appears to be little other manifestation of metabolic activity. 3. 3. Depression of spermatogenesis appears to be reversible after discontinuance of the drugs. For example, complete recovery occurred after administration of Win 13,099 for as long as 27 weeks. 4. 4. Although the exact mode of action is not known, it is postulated that the effects produced result from a direct action on the process of germinal-cell maturation, at the site of the germinal epithelium, and without concurrent pituitary suppression.

Annual patterns of luteinizing hormone, follicle stimulating hormone, testosterone and inhibin in normal men

Reproductive functions in most animals demonstrate seasonal fluctuations that allow young to be born at a time of the year favourable for their survival. Whether there is a seasonal change in the human reproductive system is unclear. In the present study, we measured serum concentrations of luteinizing hormone, follicle stimulating hormone, testosterone and inhibin in the same 16 normal men sampled monthly for 1 year. A statistically significant increase in all four measured hormones was found in June, with a nadir in August. Our findings suggest that a circannual rhythm of gonadotrophins and testicular hormones exists in normal men. The mechanism leading to this rhythm and the importance of the rhythm in human biology are unknown.

Reinitiation of sperm production in gonadotropin-suppressed normal men by administration of follicle-stimulating hormone

The specific roles of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in controlling human spermatogenesis are poorly understood. We studied the effect of an experimentally induced, selective LH deficiency on sperm production in normal men. After a 3-mo control period, five men received 200 mg testosterone enanthate (T) i.m./wk to suppress LH, FSH, and sperm counts. Then, while continuing T at the same dosage, human FSH (hFSH) was administered simultaneously to replace FSH activity, leaving LH activity suppressed. Four men received 100 IU hFSH s.c. daily plus T (high dosage hFSH) for 13-14 wk, while one man received 50 IU hFSH s.c. daily plus T (low dosage hFSH) for 5 mo. The effect on sperm production of the selective LH deficiency produced by hFSH plus T administration was assessed. In the four men who received the high dosage hFSH regimen, sperm counts were markedly suppressed during T administration alone (0.3+/-0.2 million/cm(3), mean+/-SE, compared with 94+/-12 million/cm(3) during the control period). Serum LH bioactivity (determined by in vitro mouse Leydig cell assay) was suppressd (140+/-7 ng/ml compared with 375+/-65 ng/ml during control period) and FSH levels (by radioimmunoassay) were reduced to undetectable levels (<25 ng/ml, compared with 98+/-21 ng/ml during control period) during T alone. With the addition of 100 IU hFSH s.c. daily to T, sperm counts increased significantly in all subjects (33+/-7 million/cm(3), P < 0.02 compared with T alone). However, no subject consistently achieved sperm counts within his control range. Sperm morphology and motility were normal in all four men and in vitro sperm penetration of hamster ova was normal in the two men tested during the hFSH-plus-T period. During high-dosage hFSH administration, serum FSH levels increased to 273+/-44 ng/ml (just above the normal range for FSH, 30-230 ng/ml). Serum LH bioactivity was not significantly changed compared with the T-alone period (147+/-9 ng/ml). After the hFSH-plus-T period, all four men continued to receive T alone after hFSH was stopped. Sperm counts were again severely suppressed (0.2+/-0.1 million/cm(3)), demonstrating the dependence of sperm production on hFSH administration. Serum T and estradiol (E(2)) levels increased two- to threefold during T administration alone compared with the control period. Both T and E(2) levels remained unchanged with the addition of hFSH to T, confirming the lack of significant LH activity in the hFSH preparation. In the one man who received low dosage hFSH treatment, sperm counts were reduced to severely oligospermic levels, serum FSH was suppressed to undetectable levels, and serum LH bioactivity was markedly lowered during the T-alone period. With the addition of 50 IU hFSH s.c. daily to T, sperm counts increased, to a mean of 11+/-3 million/cm(3). During this period, serum FSH levels increased to a mean of 105+/-11 ng/ml (slightly above this mans control range and within the normal adult range), while LH bioactivity remain suppressed. After hFSH was stopped and T alone was continued, sperm counts were again severely reduced to azoospermic levels. We conclude that FSH alone is sufficient to reinitiate sperm production in man during gonadotropin suppression induced by exogenous T administration. FSH may stimulate sperm production in this setting by increasing intratesticular T through androgenbinding protein production or by increasing the sensitivity of the spermatogenic response to the intratesticular T present during exogenous T administration.

Comparison of gonadal function between fertile and infertile men with varicoceles

The high prevalence of men with varicoceles who by history are fertile has led some to question the suggested causal relationship between a varicocele and male infertility. However, testicular function in these fertile men has not previously been studied in detail. Fifty-five normal fertile men, 42 fertile men with varicoceles, and 24 infertile men with varicoceles and normal female partners were studied. Semen analyses were done, baseline serum testosterone and gonadotropin levels tested and the gonadotropin response to luteinizing hormone-releasing hormone (LH-RH) measured. The infertile men with varicoceles exhibited lower sperm counts, abnormal sperm morphologic features, increased baseline serum gonadotropins, and increased gonadotropin responses to LH-RH, compared with the normal fertile men. The fertile men with varicoceles showed similar abnormalities, although this was not statistically significant in all cases. That semen and hormone abnormalities were observed in both the fertile and infertile men with varicoceles suggests that the presence of a varicocele is associated with some degree of primary testicular dysfunction, regardless of present fertility status.

Klinefelter's syndrome

Klinefelter’s syndrome (KS) is the most common sex chromosome disorder in men, affecting roughly 1 in 400–600 men throughout all ethnic groups (1,2) It is also the most common cause of primary testicular failure, resulting in impairments in both spermatogenesis and testosterone production. The hypogonadism associated with KS can range from mild to severe, leading to a marked variation in clinical presentation. Men with KS possess at least one additional or “supernumerary” X chromosome, resulting in a 47, XXY genotype. The clinical phenotype in the adult is that of severely impaired spermatogenesis (usually azoospermia) and varying degrees of hypogonadism, manifested by a tall body habitus with sparse body and facial hair, gynecomastia, diminished libido, and small testes. In childhood, common presenting features can include delayed speech development, learning difficulties at school, unusually rapid growth in mid-childhood, and truncal obesity. Laboratory analysis reveals low or low-normal serum testosterone and elevated serum gonadotropin levels, with follicle-stimulating hormone (FSH) elevated to a greater degree than luteinizing hormone (LH). The clinical diagnosis is confirmed using chromosomal analysis (karyotyping) of either peripheral blood leukocytes or tissue, which usually reveals a 47, XXY genotype, although, infrequently, additional X chromosomes may be present or an individual may be mosaic (47, XXY/46, XY). Treatment consists of testosterone therapy for improved virilization, sexual function, bone density, and quality of life. Gynecomastia is treated with cosmetic surgery after androgen replacement has begun. New approaches to the treatment of infertility, including intracytoplasmic injection of sperm aspirated from the testes, have been recently reported for KS patients and may be successful in the subset of patients in whom sperm are present on testicular biopsy. However, for most men with KS, artificial insemination with donor sperm or adoption remain the only options for fertility. This chapter summarizes the initial historical description of KS, as well as the current understanding of the pathophysiology, clinical manifestations, associated conditions, and treatment of individuals with KS. In addition, the effect of newly described assisted reproductive techniques on the potential for fertility in men with KS is discussed.

Colchicine and Testicular Function in Man

COLCHICINE, used for centuries in the therapy of gout,1 has recently been shown to be beneficial in the prevention of attacks of familial Mediterranean fever.2 , 3 Reports of a toxic effect of colc...