Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: fertilization, normal embryonic development and pregnancy occur when retrieved testicular spermatozoa are used for intracytoplasmic sperm injection

Some men with non-obstructive azoospermia harbour fully formed spermatozoa within their testicular tissue that can be used to achieve pregnancy via intracytoplasmic sperm injection (ICSI). Recently, Reijo et al. (1995) provided compelling evidence that the DAZ gene cluster is a strong candidate for one of the elusive azoospermia factors (AZF) located on the long arm of the Y chromosome. The DAZ gene cluster is deleted in 13% of azoospermic men and a small percentage of severely oligozoospermic men. Vertical transmission from father to son of AZF region deletions has also been described. Presumably these fathers were oligozoospermic. This led us to ask whether the azoospermic male with deletions of the AZF/DAZ region can also complete minimal spermatogenesis and whether any spermatozoa found could participate in fertilization, embryo development and pregnancy. Three out of six (50%) of the azoospermic men with AZF/DAZ deletions had spermatozoa identified within their harvested testicular tissue. When these spermatozoa were used for ICSI, fertilization occurred in 36% of injected oocytes. This compared favourably with testicular spermatozoa retrieved from non-obstructive azoospermic men without AZF/DAZ gene deletions. In one case, a twin conception resulted, which represents the first term pregnancy reported using spermatozoa from an AZF/DAZ deleted azoospermic male. Therefore it is necessary to take the possibility of transmission of infertility or sterility to our patients' offspring seriously when utilizing today's reproductive technologies, as spermatogenesis in men with AZF/DAZ deletions is by no means an exceptional occurrence.      

Investigation of suppression of the hypothalamic-pituitary-gonadal axis to restore spermatogenesis in azoospermic men treated for childhood cancer

BACKGROUND: Does suppression of the hypothalamic-pituitary-gonadal (HPG) axis restore spermatogenesis in men rendered azoospermic following treatment of childhood cancer? METHODS: Seven men with azoospermia secondary to treatment for childhood cancer, median age (range), 22.2 (18-25.3) years, aged 10.4 (4.4-13.3) years at original diagnosis, participated. Each subject underwent semen analysis and testicular biopsy, followed by treatment with medroxyprogesterone acetate (MPA), 300 mg i.m. repeated after 12 weeks, with 800 mg testosterone pellets s.c. on day 1 to suppress the HPG axis. Hormone and semen analysis was performed every 6 weeks for 48 weeks. A second testicular biopsy was performed at week 48. RESULTS: Before HPG axis suppression, mean +/- SEM plasma LH was 9.0 +/- 1.8 U/l, testosterone 17.9 +/- 1.5 nmol/l and FSH 22.4 +/- 4.4 U/l. Median (range) venous plasma and seminal plasma inhibin B levels were 10.0 (7.8-35) and 11.2 (7.8-770) ng/l respectively. During HPG suppression, FSH and LH levels were undetectable for > or =12 weeks followed by a gradual return to pretreatment concentrations by 48 weeks. All men remained azoospermic at study completion and complete absence of germ cells on biopsies was demonstrated by immunocytochemistry for all specimens pre- and post-HPG axis suppression. CONCLUSIONS: HPG axis suppression with MPA-testosterone for > or =12 weeks did not restore spermatogenesis in azoospermic men treated with gonadotoxic radiotherapy and chemotherapy for childhood cancer.     

Genetic evaluation of infertile men.

Recently, microdeletions in the azoospermic factor region of the Y chromosome, in addition to chromosomal anomalies, have been detected in men with azoospermia or severe oligozoospermia. In this study we evaluated the molecular and cytogenetic defects of infertile men. The frequency of Y microdeletions among 105 azoospermic, 28 oligozoospermic and 32 fertile men was tested on lymphocyte DNA using a series of 20 sequence-tagged sites. In addition, microdeletions were evaluated on testicular-derived DNA among 26 azoospermic patients who underwent testicular biopsy and in whom no sperm cells could be identified. Karyotype analysis was performed on 72 of the infertile patients. Deletions were detected in 6.7% azoospermic and 3.6% oligozoospermic men. No deletions were identified among the fertile men. Identical results were obtained with DNA derived either from lymphocytes or testicular tissue. The frequency of chromosomal aberrations in the 72 infertile patients tested (62 azoospermic, 10 oligozoospermic) was 16.6%, with a high percentage of gonosome anomalies. Additional andrological parameters (hormone values, cryptorchidism) failed to identify men at risk for having microdeletions before the test. Our findings support the recommendation to perform genetic defect screening among infertile men before their enrollment in an intracytoplasmic injection/in-vitro fertilization programme.     

Y chromosome deletions in azoospermic and severely oligozoospermic men undergoing intracytoplasmic sperm injection after testicular sperm extraction

Y chromosome deletions encompassing the AZFc region have been reported in 13% of azoospermic men and 7% of severely oligozoospermic men. We examined the impact of these Y deletions on the severity of testicular defects in 51 azoospermic men undergoing intracytoplasmic sperm injection (ICSI) after testicular sperm extraction (TESE) and 30 men with severe oligozoospermia undergoing ICSI after ejaculation of spermatozoa. In addition, five azoospermic patients shown previously to have Y chromosome deletions underwent histological evaluation of their previously obtained testis biopsy specimens. A further 27 azoospermic men underwent TESE-ICSI, but not Y chromosome DNA testing. Ten of 51 azoospermic men (20%) who underwent TESE-ICSI and Y-DNA testing were found to be deleted for portions of the Y chromosome AZFc region. Of these 10, five had spermatozoa retrievable from the testis, and in two cases the wives became pregnant. Of the 41 azoospermic men with no Y chromosome deletion, 22 (54%) had spermatozoa retrievable from the testis, and in 12 cases (29%) the wives became pregnant. Four of 30 (13%) severely oligozoospermic patients were found to be deleted for AZFc and in three (75%) of these pregnancy was achieved. The other 26 severely oligozoospermic couples who had no AZFc deletions underwent ICSI, and 12 (46%) have an ongoing or delivered pregnancy. The embryo implantation rate was not significantly different for azoospermic (22%), oligozoospermic (16%), Y-deleted (14%) or Y-intact (18%) men. Of the total of 19 infertile men who had Y chromosome deletions, 14 had deletions within Y chromosome intervals 6D-6F, in the AZFc region. Twelve of those 14 had some spermatozoa (however few in number) in the ejaculate or testis. Five of the Y-deleted men had deletions that extended more proximally on the Y chromosome, and in none of these could any spermatozoa be observed in either ejaculate or testis. These results support the concept that, in azoospermic or oligozoospermic men with Y chromosome deletions limited to intervals 6D-6F (AZFc), there are generally very small numbers of testicular or ejaculated spermatozoa. Larger Y deletions, including and extending beyond the AZFc region and encompassing more Y genes, tend to be associated with a total absence of testicular spermatozoa. In those cases where spermatozoa were retrieved, the presence of Y deletions had no obvious impact on fertilization or pregnancy rate.      

Cystic fibrosis gene mutations and infertile men with primary testicular failure

It has been proposed that the gene responsible for cystic fibrosis, called the cystic fibrosis transmembrane conductance regulator (CFTR) gene, may play an important role in the process of spermatogenesis. A group of azoospermic men with primary testicular failure underwent CFTR mutation analysis, including assessment of the intron 8 polythymidine tract (IVS8-T tract). An association was not found between CFTR mutations or the 5T variant of the IVS8-T tract and the primary testicular failure phenotype. This finding suggests that CFTR does not play a significant role in the aetiopathogenesis of primary spermatogenic dysfunction. Therefore, the abnormal testicular histological findings in some post-pubertal men with cystic fibrosis may be a result of nutritional deficiency or testicular obstruction rather than a primary defect in spermatogenesis. In addition, the decreased sperm count in oligozoospermic men with CFTR mutations may be secondary to partial reproductive tract obstruction and not abnormal spermatogenesis. Lastly, routine screening of men with primary testicular failure for CFTR gene mutations is not warranted.     

Idiopathic hirsutism--an ovarian abnormality.

We investigated increased production of testosterone and androstenedione in 44 women with unexplained adult-onset hirsutism, 41 of whom had normal-sized ovaries. Twenty women in this group had at least 50 per cent suppression of plasma testosterone and androstenedione after four to five days of dexamethasone. Testosterone and androstenedione values in ovarian-vein effluents were higher than those of their adrenal veins. We calculated adrenal secretion rates of both androgens in each patient by relating the adrenal gradients to those of cortisol. In 42 of the hirsute women, including those whose androgens were suppressed after dexamethasone, the ovaries were the predominant source of androgen production. The women with dexamethasone suppression had milder degrees of virilism and lower production rates of testosterone and androstenedione. We conclude that the ovaries are the source of excessive androgens in most women with unexplained hirsutism, and that corticoid-suppressible patients have milder forms of ovarian hyperandrogenism.     

男性不育患者Y染色体微缺失筛查方法的建立和初步应用

目的 建立一套Y染色体微缺失的多重PCR筛查方法，对无精症或少精症男性不育患者进行Y染色体微缺失的常规筛查。方法 建立5套稳定和可靠的多重PCR筛查方法，对进行单精子卵细胞浆注射治疗的87例无精症和少精症患者及进行睾丸活检的30例无精症患者做Y染色体微缺失的检测。结果 共有19例发现微缺失(16．2％)，其中61例少精症患者中发现11例(18．0％)，56例无精症患者中发现8例(14．3％)。结论 Y染色体微缺失的多重PCR筛查方法是易行和可靠的，对无精症和少精症患者有必要进行Y染色体微缺失的常规筛查。     

The significance of anti-Müllerian hormone concentration in seminal plasma for spermatogenesis

BACKGROUND: The function of anti-Müllerian hormone (AMH) in seminal plasma in adulthood is uncertain. We examined the significance of seminal AMH for spermatogenesis. METHODS: We measured seminal concentrations of AMH in 39 oligozoospermic men (mean age +/- SD, 32.7 +/- 4.3 years) and 10 normal volunteers to examine the association of seminal AMH with spermatogenesis. The seminal concentrations of AMH in oligozoospermic men (149.3 +/- 254.0 pmol/l) were significantly lower than in normal men (249.0 +/- 167.7 pmol/l; P +/- 0.0337). Seminal AMH concentration correlated significantly with sperm concentration (r = 0.339, P = 0.0350) and mean testicular volume (r = 0.440, P = 0.246). The serum concentration of LH (r = - 0.365, P = 0.0241), but not FSH, testosterone or estradiol, correlated significantly with AMH concentration in seminal plasma. CONCLUSIONS: AMH in seminal plasma may be important for sperm production, and is a good marker for Sertoli cell development.     

Male hormonal contraception: concept proven, product in sight?

Current male hormonal contraceptive (MHC) regimens act at various levels within the hypothalamic pituitary testicular axis, principally to induce the withdrawal of the pituitary gonadotrophins and in turn intratesticular androgen production and spermatogenesis. Azoospermia or severe oligozoospermia result from the inhibition of spermatogonial maturation and sperm release (spermiation). All regimens include an androgen to maintain virilization, while in many the suppression of gonadotrophins/spermatogenesis is augmented by the addition of another anti-gonadotrophic agent (progestin, GnRH antagonist). The suppression of sperm concentration to 1 x 10(6)/ml appears to provide comparable contraceptive efficacy to female hormonal methods, but the confidence intervals around these estimates remain relatively large, reflecting the limited number of exposure years reported. Also, inconsistencies in the rapidity and depth of spermatogenic suppression, potential for secondary escape of sperm into the ejaculate and onset of fertility return not readily explainable by analysis of subject serum hormone levels, germ cell number or intratesticular steroidogenesis, are apparent. As such, a better understanding of the endocrine and genetic regulation of spermatogenesis is necessary and may allow for new treatment paradigms. The development of an effective, consumer-friendly male contraceptive remains challenging, as it requires strong translational cooperation not only between basic scientists and clinicians but also between public and private sectors. At present, a prototype MHC product using a long-acting injectable testosterone and depot progestin is well advanced.     

Suppression of spermatogenesis to azoospermia by combined administration of GnRH antagonist and 19-nortestosterone cannot be maintained by this non-aromatizable androgen alone.

BACKGROUND: For male hormonal contraception, combined administration of gonadotrophin-releasing hormone (GnRH) antagonists and androgens effectively suppresses spermatogenesis to azoospermia. In non-human primates this suppression can be maintained more easily by androgens alone. METHODS: A clinical trial with six healthy volunteers was performed to test this approach in man. Loading doses of 10 mg/day of the GnRH antagonist cetrorelix were given subcutaneously for 5 days, followed by maintenance doses of 2 mg/day up to week 12. At 2 weeks after the first GnRH antagonist injection, androgen substitution was initiated with a loading dose of 400 mg 19-nortestosterone hexyloxyphenylpropionate (19NT-HPP) intramuscularly, followed by injections of 200 mg 19NT-HPP every 3 weeks up to week 26. RESULTS: Serum concentrations of LH, FSH and testosterone were effectively suppressed by cetrorelix administration. Within 12 weeks, azoospermia was achieved in all six volunteers. After cessation of cetrorelix injections in week 12, gonadotrophins and testosterone increased significantly despite continued 19NT-HPP injections. In parallel, spermatogenesis was restimulated in five of six volunteers. CONCLUSIONS: Combined administration of cetrorelix and 19NT-HPP leads to azoospermia within 3 months. However, complete azoospermia cannot be maintained by continued injections of the non-aromatizable 19NT-HPP alone.     

FISH analysis of chromosome X,Y and 18 abnormalities in testicular sperm from azoospermic patients

BACKGROUND: Sperm extracted from testicular biopsies of azoospermic men can successfully be used for ICSI. The concern exists that testicular sperm from azoospermic men suffering from severe testicular failure may have a higher frequency of aneuploidy, which may lead to an increased risk for chromosomally abnormal offspring. METHODS: Testicular sperm from patients showing spermatogenic failure (n = 17) and from patients with normal spermatogenesis (n = 26) were analysed by fluorescence in-situ hybridization (FISH). Numerical chromosomal abnormalities for chromosomes X, Y and 18 were evaluated by FISH in a total of 1697 testicular sperm derived from 43 azoospermic patients. RESULTS: No difference was observed between the frequency of chromosomal abnormalities in testicular sperm from patients with normal spermatogenesis (5.6%) and from patients with spermatogenic failure (8.2%). However, the frequency of aneuploidy for chromosome 18 was higher in the group of azoospermic patients with spermatogenic failure than in the group with normal spermatogenesis (3.2 versus 1.3%). Within the obstructive group, sex chromosome aneuploidy (4.5%) occurred more frequently than chromosome 18 aneuploidy (1.3%; P < 0.001). Among testicular sperm derived from patients with spermatogenic failure, sex chromosomal aneuploidy (5.8%) was similar to that for chromosome 18 (3.2%). CONCLUSIONS: So far, no difference in the total frequency of chromosomal abnormalities has been observed between patients with normal spermatogenesis and patients with severe testicular failure. However, aneuploidy for chromosome 18 was higher in the group with spermatogenic failure.     

Isolation, purification and assessment of viability of spermatogenic cells from testicular biopsies of azoospermic men

The success of spermatid microinjection has generated many concerns. In particular, there is a lack of appropriate methodology for the isolation of large homogeneous populations of spermatids, with minimum loss of viability, from the testicular tissue of azoospermic men. Here we have compared two different isolation methods -- velocity sedimentation under unit gravity (VSUG) combined with discontinuous Percoll centrifugation (DPC), and separation with fluorescent-activated cell sorter (FACS) using light in the visible range -- to determine the most suitable method for the isolation of spermatids. Total mixed cell count/gram of testicular parenchyma was significantly higher in obstructive azoospermic men compared with non-obstructive azoospermic men (P < 0.001). The results of the comparison showed that in obstructive azoospermic patients the difference in the yields of primary spermatocytes produced by the two techniques was not significant, but for round and elongating spermatids the FACS separation proved to be the better method (P < 0.001). Similarly, in non-obstructive azoospermic patients, FACS separation proved to be superior, giving increased yields of primary spermatocytes and round and elongating spermatids compared with VSUG combined with DPC method (P < 0.001). More than 99 % of the separated cells retained their viability after FACS separation. As large homogeneous populations of viable spermatids can be separated with FACS in a relatively short period of time, FACS separation is the most suitable method for the isolation of spermatids from testicular biopsy tissue.      

Biochemical and endocrine heterogeneity in the complete form of testicular feminization syndrome

A familial variant of male pseudohermaphroditism different from the classical form of the complete testicular feminization syndrome was studied. The three affected 46, XY sibling (16,18 and 20 years old) exhibited female phenotype identical to that of a 17 years old patient with the classical form, included as a control. The major endocrine and biochemical differences observed in this family, as compared with the classical form, includes: a. Markedly elevated serum levels of LH and FSH; b. Non-elevated serum testosterone levels; c. Poor testicular hCG responsiveness; d. Abnormally elevated baseline and hCG-stimulated androstenedione: testosterone ratio; e. Slight pituitary responsiveness to androgens; f. presence of residual androgen uptake by cultured fibroblasts derived from genital skin. These differences were more evident in the two older patients. All subjects presented a lack of nitrogen retention following testosterone administration. These results were interpreted as demonstrating a testicular impairment of testosterone biosynthesis in the older subjects of this family, which resulted in an unusual gonadotropin profile. The altered androstenedione: testosterone ratio suggests a secondary partially decreased activity of testicular 17-hidroxysteroid dehydrogenase, as demonstrated in TFM mice and rats. The overall data indicate an age-dependent variability in the expression of androgen insensitivity in this family, thus demonstrating the wide biochemical heterogeneity of the androgen resistant syndromes.     

Effect of androgens on the cranial suspensory ligament and ovarian position

Androgens have been postulated to have a major role in testicular descent via regression of the cranial suspensory ligament, which in normal rodents anchors the ovary to the retroperitoneum near the lower pole of the kidney. This study aimed to quantitate the degree of descent of the foetal ovary in androgen‐treated female mice to determine the role of androgens in regression of the cranial suspensory ligament and descent of the testis. Time‐pregnant mice were injected with testosterone propionate or methyl testosterone (2.5–3.0 mg) in vehicle on day 13 or 14. Control animals received vehicle only. Newborn mice were anaesthetised and dissected for macroscopic anatomy of the ovary, which was quantified by measuring the vertical distance from the lower pole of the kidney to the lower pole of the ovary. Histological analysis was also performed. The external genitalia were masculinised in all females exposed to prenatal androgens. The ovaries of treated animals were mobile, with no cranial suspensory ligament, and located slightly caudal to the kidney. Wolffian duct structures were identifiable, but the gubernaculum was qualitatively unchanged compared with control females. The ovary was displaced caudally (P< 0.001), but only 15–25% of the distance to the lower abdomen. Exogenous androgens induce regression of the cranial suspensory ligament, causing the ovary to be more mobile and lower in the abdominal cavity. However, since the testicular position at birth is at or below the bladder neck, androgen‐mediated regression of the cranial suspensory ligament is only an adjunct to the control of transabdominal testicular descent. Anat Rec 255:306–315, 1999. © 1999 Wiley‐Liss, Inc.     

Can biological or clinical parameters predict testicular sperm recovery in 47,XXY Klinefelter's syndrome patients?

BACKGROUND: Contradictory results are available regarding prediction of testicular sperm extraction in 47,XXY patients. This study, therefore, aimed at assessing the availability of testicular sperm and evaluates clinical parameters predicting successful sperm retrieval in azoospermic 47,XXY Klinefelter's syndrome patients. METHODS: Sperm recovery procedures were performed in 50 non-mosaic azoospermic Klinefelter patients. The facial hair pattern and the presence of gynaecomastia in men with successful and unsuccessful sperm recovery were compared using Fisher's exact test. The predictive value of clinical parameters such as age, testicular volume, FSH, FSH:LH ratio, testosterone and androgen sensitivity index (LH x testosterone) for successful testicular sperm retrieval was evaluated using the receiver operating characteristics (ROC) curve analysis. RESULTS: In 24 patients (48%) testicular sperm were recovered. Ninety-four per cent of the men in whom sperm was found had a normal facial hair pattern compared to 93% in whom no sperm was recovered (not significant, NS). Seventeen percent of the men with successful testicular sperm extraction had gynaecomastia compared to 31% of the men with failed testicular sperm extraction (NS). The mean testicular volume of the largest testis in patients with sperm found was 4.2 ml compared to 3.6 ml in patients with no sperm found (NS). The mean FSH and testosterone values in patients with sperm recovered were 31.2 IU/l and 3.1 ng/ml versus 40.4 IU/l (P = 0.04) and 3.2 ng/ml (NS) in patients without sperm recovered. All examined clinical and biological parameters failed to predict the outcome of the testicular sperm extraction using ROC curve analysis. CONCLUSION: As in the general population of men with non-obstructive azoospermia, there are currently no clinical parameters predicting successful sperm retrieval in the subpopulation of patients with non-mosaic Klinefelter syndrome.     

Quantitative analysis of mast cells in testicular aspiration cytology smears in azoospermic males

Quantitative estimation of mast cells was done in testicular aspiration cytology smears of 90 azoospermic males. Cases included normal spermatogenesis (32), Sertoli cell only (38), late maturation arrest (16), and early maturation arrest (4). The pooled number of mast cells in 20 standard fields in Sertoli cell only and late maturation arrest cases were significantly higher than that of normal spermatogenesis (P < .001 and P < .01 respectively). Aggregates of mast cells were found around the seminiferous tubules in Sertoli cell only cases. The findings suggest that increased number of mast cells may be the cause or effect of testicular damage in idiopathic male infertility.     

Oral desogestrel with testosterone pellets induces consistent suppression of spermatogenesis to azoospermia in both Caucasian and Chinese men

BACKGROUND: Effective hormonal male contraception requires a high prevalence of spermatogenic suppression, which has proved particularly difficult in Caucasian populations. We have investigated the combination of oral desogestrel with depot testosterone in Caucasian and Chinese men. METHOD: Thirty men in Edinburgh and 36 men in Shanghai received 150 or 300 microg desogestrel p.o. daily for 24 weeks with 400 mg testosterone pellets s.c. on day 1 and at 12 weeks. RESULTS: Eight men withdrew before completing 24 weeks treatment. Testosterone concentrations remained within the normal range. Spermatogenesis was profoundly suppressed in all men. Azoospermia was achieved by a higher proportion of men in the 300 microg desogestrel group: 28/28 men versus 22/31 men (P < 0.05). All Caucasian men in the 150 microg group achieved sperm concentrations of < 1 x 10(6)/ml whereas three men in the Shanghai group maintained sperm concentrations of > 3 x 10(6)/ml. Fifteen men continued on this regimen for a subsequent 24 weeks: all remained azoospermic for the duration of treatment. High-density lipoprotein cholesterol fell by 15% in Caucasian men, but was unchanged in the Chinese men; both groups showed some weight gain. CONCLUSION: This combination of oral desogestrel with depot testosterone maintains physiological testosterone concentrations with consistent suppression of spermatogenesis to azoospermia in both Caucasian and Chinese men and therefore has many of the properties necessary for a contraceptive preparation for men.     

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.     

Effect of interferon alpha on high serum androgen concentrations in HIV positive men with Kaposi's sarcoma.

AIM: To measure serum androgen concentrations in men with HIV related Kaposi's sarcoma (KS) who had been treated with recombinant interferon (IFN) alpha-2a to determine the role of androgens on the development of KS lesions. METHODS: 32 men with HIV related KS who had been treated with IFN were studied: 24 men in complete KS remission and eight not in remission. Serum androgen concentrations were determined before, during, and after IFN treatment and correlated with clinical remission. RESULTS: All patients in complete KS remission had lower serum androgen concentrations following IFN treatment: -51% for dehydroepiandrosterone (DHEA) (p < 0.0001); -38% for DHEA sulphate (p < 0.002);-39% for androstenedione (p < 0.002); and -44% for testosterone (p < 0.007). These decreases brought the serum concentrations to about normal levels. However, IFN had varying effects on serum androgen concentrations in the men not in remission: a small decrease, a large increase in one androgen, or no change in serum androgens. CONCLUSIONS: The association between serum androgen levels and the progression or remission of HIV associated KS suggests that androgens affect the development of KS lesions. A clear understanding of the changes in the androgen environment may provide a sound basis for the development of new therapeutic strategies.