Investigation of hormonal male contraception in African men: suppression of spermatogenesis by oral desogestrel with depot testosterone

BACKGROUND: Suppression of spermatogenesis to azoospermia is required for effective hormonal male contraception, but the degree of suppression varies between ethnic groups. We here report the first study of hormonal suppression of spermatogenesis in two African centres using a regimen of oral progestogen with depot testosterone. METHODS A total of 31 healthy men (21 black) were recruited in Cape Town and 21 men in Sagamu, Nigeria. Subjects were randomized to take either 150 or 300 micro g desogestrel daily p.o. with testosterone pellets. In Cape Town, desogestrel was administered for 24 weeks with 400 mg testosterone re-administered 12 weekly. In Sagamu, desogestrel was administered for 52 weeks with 200 mg testosterone (later increased to 400 mg) re-administered 12-weekly. RESULTS: In Cape Town, 22 men completed at least 20 weeks treatment. Azoospermia was achieved in 8/10 and 8/12 men in the 150 micro g and 300 micro g desogestrel groups. Four men in Sagamu withdrew. Azoospermia was achieved in all 17 men in the two groups. There were no significant changes in lipoprotein or haemoglobin concentrations in any group. CONCLUSION: These data demonstrate that the combination of oral desogestrel with depot testosterone is an effective regimen for suppression of spermatogenesis in African as in Caucasian and Chinese men, with azoospermia achieved in a total of 83/98 (85%) men.     

Dose-finding study of oral desogestrel with testosterone pellets for suppression of the pituitary-testicular axis in normal men

Prototype hormonal male contraceptive regimens generally achieve only incomplete suppression to azoospermia with potentially adverse metabolic effects. We have carried out a short-term dose-finding study to investigate the potential of an oral gestogen, desogestrel, with testosterone pellets. Normal men received a single dose of 300 mg testosterone with 75 microg, 150 microg or 300 microg desogestrel daily for 8 weeks (n = 10 per group). LH and FSH were rapidly suppressed, with little difference between groups. Testosterone concentrations fell slightly during treatment with evidence of a linear dosage effect. Plasma inhibin B showed minor changes, but in seminal plasma it was suppressed, becoming undetectable in all men in the 300 microg desogestrel group. There were no significant changes in lipoproteins, fibrinogen or sexual behaviour during treatment, and minor falls in haematocrit and haemoglobin concentration. Sperm concentration fell in a dose-dependent manner, with three men, one man and seven men in the three groups respectively achieving severe oligozoospermia (<3 x 10(6)/ml), and three men achieving azoospermia in the 300 microg group despite the short duration of the study. The combination of oral desogestrel with depot testosterone thus results in profound suppression of gonadotrophin secretion without adverse metabolic or behavioural effects. Desogestrel with a long-acting testosterone preparation is a promising approach to hormonal male contraception.     

An investigation of the effectiveness of testosterone implants in combination with the prolactin inhibitor quinagolide in the suppression of spermatogenesis in men

BACKGROUND: Administration of testosterone inhibits gonadotrophin secretion and spermatogenesis in men but the degree of response is highly variable. This treatment also stimulates prolactin, itself a progonadal hormone in animals. This study investigated whether concomitant suppression of prolactin (PRL) with the non-ergot, dopamine receptor agonist quinagolide (Q), would enhance the efficacy of testosterone in its inhibition of spermatogenesis in healthy eugonadal men. METHODS: A total of 46 men were randomized to three treatment groups: Group 1, T1200: 1200 mg testosterone implant plus daily oral placebo; Group 2, T1200 + Q: 1200 mg testosterone plus oral Q 75 microg/day; Group 3, T800 + Q: testosterone 800 mg plus oral Q 75 microg/day. After an initial pre-treatment period of 4 weeks, subjects were treated for 24 weeks followed by an 8-week recovery period. RESULTS: The total numbers of subjects that achieved severe oligospermia (< or =10(6)/ml including azoospermia) from weeks 8-16 were 11/13 (85%), 11/12 (92%), 8/13 (61.5%) in the three groups respectively. CONCLUSIONS: The results show that inhibition of PRL does not to confer additional efficacy in spermatogenic suppression in men. However, Q did not totally block PRL secretion in the subjects, possibly because testosterone replacement itself stimulated PRL by a direct action on the lactotroph, thus the effectiveness of dual inhibition of gonadotrophin and PRL could not be fully investigated.     

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.     

Low dose of cyproterone acetate and testosterone enanthate for contraception in men

After a control phase, 10 normal men received cyproterone acetate (CPA) at a dose of 25 mg/day (CPA-25; n=5) or 12.5 mg/day (CPA-12.5; n=5) plus testosterone enanthate (TE) 100 mg/week, for 16 weeks. Throughout the study sperm counts were performed every 2 weeks, and luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, biochemical and haematological tests were performed every 4 weeks. All five men in group CPA-25 and three men in group CPA-12.5 achieved azoospermia. One man in group CPA-25 was azoospermic by week 12 of hormone administration, but had a sperm count of 0.1 x 10(6)/ml at week 16. Time to azoospermia was 9.0+/-1.3 and 8.7+/-0.7 weeks in groups CPA- 25 and CPA-12.5 respectively. Gonadotrophins were decreased by week 4 of hormone administration, remained around the minimum detectability of the assay for the duration of hormone administration and returned to baseline after stopping hormone administration. Testosterone values did not change. No change in any biochemical parameters was found. Haematological parameters were decreased at week 16 of hormone administration and returned to baseline after stopping hormone administration. In conclusion, these results suggest that an hormonal regimen consisting of testosterone plus a progestin with anti- androgenic properties holds promise as an effective, safe and reversible male contraceptive.      

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.     

A multicentre study investigating subcutaneous etonogestrel implants with injectable testosterone decanoate as a potential long-acting male contraceptive

BACKGROUND: The combination of etonogestrel implants with injectable testosterone decanoate was investigated as a potential male contraceptive. METHODS: One hundred and thirty subjects were randomly assigned to three treatment groups, all receiving two etonogestrel rods (204 mg etonogestrel) and 400 mg testosterone decanoate either every 4 weeks (group I, n = 42), or every 6 weeks (group II, n = 51) or 600 mg testosterone decanoate every 6 weeks (group III, n = 37) for a treatment period of 48 weeks. RESULTS: One hundred and ten men completed 48 weeks of treatment. Sperm concentrations of <1 x 10(6)/ml were achieved in 90% (group I), 82% (group II) and 89% (group III) of subjects by week 24. Suppression was slower in group II, which also demonstrated more frequent escape from gonadotrophin suppression than groups I and III. Peak testosterone concentrations remained in the normal range throughout in all groups. Mean trough testosterone concentrations were initially subphysiological but increased into the normal range during treatment. Mean haemoglobin levels increased in group I, and a non-significant increase in weight and decline in high-density lipoprotein cholesterol was observed in all groups. Fourteen subjects discontinued treatment due to adverse events. CONCLUSIONS: Subcutaneous etonogestrel implants in combination with injectable testosterone decanoate resulted in profound suppression of spermatogenesis that could be maintained for up to 1 year. Efficacy of suppression was less in group II, probably due to inadequate testosterone dosage. This combination has potential as a long-acting male hormonal contraceptive.     

Partial deletions in the AZFc region of the Y chromosome occur in men with impaired as well as normal spermatogenesis

BACKGROUND: Partial deletions of the AZFc region of the Y chromosome were reported to be a significant risk factor for oligo-/azoospermia. In this study, we assessed the occurrence and frequency of partial AZFc microdeletions in patients with spermatogenic failure and in controls with normal spermatogenesis. METHODS: In a retrospective study design, gr/gr, b1/b3 and b2/b3 deletions were analysed by multiplex PCR in 170 men with normal spermatogenesis and 348 men with non-obstructive oligo-/azoospermia. RESULTS: gr/gr deletions were found in 14 men with oligozoospermia or azoospermia (4.0%) and in three normozoospermic men (1.8%) (NS). b1/b3 deletions were found both in controls (n=1) and in patients (n=1). b2/b3 deletions were significantly more frequent in the normozoospermic (five out of 170) than in the oligo-/azoospermic men (two out of 348). Three novel partial AZFc deletion patterns were found in four oligo-/azoospermic men. No correlation with semen or other clinical parameters was found. CONCLUSIONS: The frequency of gr/gr deletions is not significantly increased in men with oligo-/azoospermia, indicating that they are not sufficient per se to cause spermatogenetic impairment and infertility. b1/b3 and b2/b3 deletions are probably irrelevant for spermatogenesis. Novel deletion patterns found exclusively in infertile men suggest that other, still unexplored partial deletions might contribute to spermatogenic failure.     

Increased oestradiol level in seminal plasma in infertile men

Seminal hormonal patterns in fertile and infertile men wereinvestigated. Follicle-stimulating hormone (FSH), luteinizinghormone (LH), prolactin, testosterone and oestradiol were assessedby radioimmunoassay, and dehydroepiandrosterone sulphate (DHAS)by bioluminescence assay, on blood and seminal plasma of 23fertile men and 83 infertile men. For fertile men, mean FSH,LH, testosterone and DHAS concentrations were lower and meanoestradiol was higher in seminal than in blood plasma; prolactindid not differ. For infertile men, mean seminal FSH and LH showeda moderate but significant increase compared with fertile men;testosterone, DHAS and prolactin did not differ but mean seminaloestradiol was significantly increased. Of the infertile men,53% had seminal oestradiol concentration above the 90^th percentilevalue for fertile men. The meaning of this seminal oestradiolincrease is unclear since it is not known whether it is thecause or the consequence of the alteration of spermatogenesisin infertile men. Further studies are required to explore thepossible therapeutic implications.     

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.     

Response of serum inhibin B and pro-alphaC levels to gonadotrophic stimulation in normal men before and after steroidal contraceptive treatment

BACKGROUND: Testicular regulation of inhibin B may be influenced by the germ cell complement. METHODS: We examined the effects of gonadotrophin stimulation on serum inhibin B and pro-alphaC in 25 normal men at (i) control (stimulation test 1), (ii) after spermatogenic suppression induced by testosterone plus progestin treatment (stimulation test 2), and (iii) during spermatogenic recovery induced by FSH and/or hCG treatment (stimulation test 3). For each test, subjects received a single injection of 1200 IU FSH or 5000 IU hCG or both. RESULTS: Inhibin B and pro-alphaC fell with spermatogenic suppression (75 and 51% of pre-treatment baseline respectively, P < 0.05). Inhibin B response to FSH (130-144%) was similar in controls and after germ cell suppression. Pro-alphaC response after germ cell suppression compared with control was significantly increased (P < 0.05) with both FSH (210-229% versus 140-185%) and hCG (254-261% versus 145%). All treatments partially restored spermatogenesis with no clear relationship apparent between inhibin B and sperm count. CONCLUSIONS: We conclude that: (i) serum inhibin B and pro-alphaC are only partially gonadotrophin dependent, (ii) spermatogenic suppression does not modify inhibin B response to FSH but enhances pro-alphaC response to both FSH and hCG, and (iii) inhibin B is a poor marker of spermatogenesis in this model of gonadotrophic manipulation in normal men.     

Endocrinology: Follicle stimulating hormone-granulosa cell axis involvement in the antifolliculotrophic effect of low dose mifepristone (RU486)

This study was designed to assess the involvement of folliclestimulating hormone (FSH)—granulosa and luteinizing hormone(LH)—theca axes in the antifolliculotrophic effect ofmifepristone. Plasma gonadotrophins, including plasma LH bioactivityand pulsatility, oestradiol, testosterone and inhibin concentrations,and follicular growth were monitored in volunteer women treatedwith placebo or mifepristone in two consecutive cycles. Mifepristonewas given either as a single dose of 5 mg (n = 7) when the leadingfollicle had reached a diameter between 12 and 14 mm, or asa multiple dose of 5 mg/day for 3 days, beginning when the leadingfollicle had reached a diameter between 14 and 16 mm (n = 5)or between 6 and 11 mm (n = 5). Following the single dose ofmifepristone, follicular growth and the accompanying increasein plasma oestradiol were arrested at 12 and 36 h respectivelywithout changes in gonadotrophin or testosterone serum concentrations.The 3 day regimen arrested follicular growth and oestradiolrise and decreased plasma inhibin concentrations when follicleswere larger than 12 mm at the onset of treatment. These resultsindicate that the antifolliculotrophic action of mifepristoneis associated with a selective compromise of the FSH—granulosaaxis of dominant follicles that have passed a critical stageof growth.     

Depot testosterone with etonogestrel implants result in induction of azoospermia in all men for long-term contraception

BACKGROUND: Combined testosterone and progestogen preparations are a promising approach to male hormonal contraception. We investigated the effect of s.c. etonogestrel with depot testosterone on spermatogenesis in normal men over a period of 48 weeks. METHODS: Fifteen healthy men received three s.c. 68 mg etonogestrel implants. Testosterone pellets (400 mg) were administered at 12 weekly intervals. RESULTS: Nine men completed 48 weeks of treatment. Four subjects chose to discontinue after 6 months, one man withdrew from the study early for personal reasons and one was withdrawn due to illness. Sperm concentrations of <1 x 10(6)/ml were achieved in all men by 16 weeks of treatment. All men became azoospermic, although the time to achieve this varied from 8 to 28 weeks. Azoospermia was maintained in eight of the nine men treated for 48 weeks, one subject showing partial recovery from 40 weeks. Testosterone levels remained in the physiological range throughout. Treatment did not result in weight gain, change in body composition or decline in high-density lipoprotein cholesterol concentrations. CONCLUSIONS: The combination of three etonogestrel implants with depot testosterone results in rapid and consistent suppression of spermatogenesis. This can be maintained for up to 1 year and may therefore be a suitable approach for a long-acting male hormonal contraceptive.     

Serum luteinzing hormone pulsatility and intratesticular testosterone and oestradiol concentrations in idiopathic infertile men with high and normal fofficle stimulating hormone serum concentrations

The purpose of the study was to evaluate pulsatile luteinizinghormone (L release and intratesticular concentrations of testosteroneand oestradlol in infertile men, to determine if alterationsin gonadotrophin secretion are associated with changes in thetesticular concentrations of steroids. Patients with idiopathicoligo/azoospermia were divided into a high follicle stimulatinghormone (FSH) group (n=5) and a normal FSH group (n = 6). Bloodsamples were taken every 15 mm for 6 h to determine LH, FSH,testosterone, oestradiol, sex hormone binding globulin, bioactiveLH and bioavailable testosterone. The patients underwent a bilateraltesticular biopsy for histological assessment and to determinetestosterone and oestradiol concentrations. Serum measure mentswere compared with those of seven fertile men. The high FSHgroup had a higher concentration of serum UI and oestradiolthan normal men (P < 0.01) and showed a lower frequency ofLII pulses than the normal FSH group and control men (P <0.01). Intratesticular oestradiol was higher in the high FSHgroup (P < 0.001), with a lower testosterone/oestradlol ratio(P < 0.01). Patients showed a negative correlation betweenthe serum testosterone/LH ratio and FSH (r = -–0.75; P< 0.01) and a positive correlation between the testicularoestradiol concentration and serum FSH (r=0.86; P<0.01).The histopathological examination only showed a smaller tubediameter in the high FSll group (P < 0.05). These data seemto indicate that a higher intratesticular concentration of oestradiolwith a lower testosterone/oestradiol ratio in the high FSH groupcould have a deleterious effect on spermatogenesis.     

Acceptability of an injectable male contraceptive regimen of norethisterone enanthate and testosterone undecanoate for men

BACKGROUND: We assessed attitudes towards and acceptability of male hormonal contraception among volunteers participating in a clinical trial of a prototype regimen, consisting of progestin and testosterone injections. METHODS: After completing screening, eligible men were randomly assigned to the no-treatment group (n = 40) or to receive injections of norethisterone enanthate and testosterone undecanoate or placebo at different intervals (n = 50) according to a blocked randomization list. They underwent self-administered questionnaires. RESULTS: The average age of the participants was approximately 28 years; most were involved in a stable relationship and had no children. Ninety-two percentage of the respondents thought that men and women should share responsibility for contraception and 75% said they would try a hormonal contraceptive if available. At the end of the treatment phase, 66% of the participants said that they would use such a method, and most rated its acceptability very highly; none reported it to be unacceptable. The injections themselves were indicated as the biggest disadvantage. No significant changes in sexual function or mood states were detected among the men who underwent hormone injections. CONCLUSIONS: The contraceptive tested in this study was well accepted by the participants over the course of 1 year.     

Rates of suppression and recovery of human sperm output in testosterone-based hormonal contraceptive regimens

BACKGROUND: Practical hormonal male contraceptive regimens are likely to have delayed onset and offset of reliable contraception dictated by the length of the spermatogenic cycle and clearance rate of pre-formed sperm from the ductular system. While delayed onset of contraceptive efficacy is an accepted feature of vasectomy, reliable time estimates for a hormonal male contraceptive of time to onset and offset of reliable contraception and of resumption of normal male fertility are required. METHODS AND RESULTS: We utilized the sperm output data from three male contraceptive efficacy studies to define quantitative estimates of suppression and recovery rates from an androgen alone (testosterone enanthate) and an androgen/progestin (testosterone/depot medroxyprogesterone acetate) study. Using nearly 14,000 semen samples from World Health Organization (WHO) studies #85921 and #89903 with identical protocols, the rate of suppression of sperm output was best modelled as a two-parameter, single exponential decay function with effective half-time to suppression of 5.5 weeks and times of 6.8 weeks to 10 x 10(6)/ml, 8.7 weeks to 5 x 10(6)/ml, 10.0 weeks to 3 x 10(6)/ml and 13.0 weeks to 1 x 10(6)/ml. The rate of recovery using absolute sperm concentration was best modelled as a three-parameter, sigmoidal curve with effective time to reach half of the recovery plateau of 10.5 weeks and times of 9.0 weeks to 3 x 10(6)/ml, 9.9 weeks to 5 x 10(6)/ml, 11.5 weeks to 10 x 10(6)/ml, and 13.6 weeks to 20 x 10(6)/ml. Using relative sperm output, defined as a percentage of the participants' own baseline, recovery approached an asymptotic plateau of approximately 85% of geometric mean pre-treatment sperm concentration. In the combination androgen/progestin study, suppression rate was significantly faster (effective time to reach half maximal suppression of 3.0 weeks) and recovery significantly slower (effective time to reach half of recovery plateau of 14.7 weeks) and less complete (asymptotic recovery plateau of 43% of baseline) than in the androgen-alone WHO studies. CONCLUSION: These findings therefore provide large sample estimates of the suppression and recovery rates from an androgen-alone hormonal male contraceptive regimen as a basis for comparison with other second-generation combination androgen/progestin regimens that are the most promising approach to developing practical male hormonal regimens.     

Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility.

Deletion of the AZFc region of the Y chromosome is the most frequent molecularly defined cause of spermatogenic failure. We report three unrelated men in whom azoospermia or severe oligozoospermia was caused by de-novo AZFc deletions, and who produced sons by intracytoplasmic sperm injection (ICSI). We employed polymerase chain reaction (PCR) assays to examine the Y chromosomes of their four infant sons. All four sons were found to have inherited the Y chromosome deletions. Such sons are likely to be infertile as adults. This likelihood should be taken into account when counselling couples considering ICSI to circumvent infertility due to severe oligozoospermia or non-obstructive azoospermia.     

Maturation phenotype of Sertoli cells in testicular biopsies of azoospermic men

The involvement of Sertoli cells in different spermatogenic impairments has been studied by an immunohistomorphometric technique using cytokeratin-18 (CK-18) as a marker for immature Sertoli cells. CK-18 is known to be expressed in Sertoli cells during prenatal and prepubertal differentiation and is normally lost at puberty. Forty-nine azoospermic men were included in the current study. Quantitative measurements on testicular biopsies revealed the highest CK-18 expression in the mixed atrophy biopsies (22 men), a lower expression in the Sertoli cell-only (SCO) biopsies (12 men), and minimal residual staining in the group considered as representing normal spermatogenesis (six obstructive azoospermia patients). The cytokeratin immunopositive-stained tubules were associated either with arrest in spermatogenesis or with SCO. Examination of sections from nine men with microdeletions in the AZF region of the Y chromosome revealed that these men were either negative for CK-18 expression or showed only weak residual staining. This may suggest that the spermatogenic defect in the AZF-deleted men originates in the germ cell and has no impact on Sertoli cell maturation. The cause that determined the spermatogenic defect in the other cases of male infertility with high CK-18 expression may have damaged both the Sertoli and the germ cells.     

A reappraisal of the feedback effects of oestradiol uppm luteinizing hormone surge

The objective of this study was to assess the temporal relationshipsof serum oestradiol and luteinizing hormone (LH) with regardto the feedback mechanism leading to the LH surge. Daily measurementsof oestradiol, LH and follicle stimulating hormone were madein 65 women with ovarian failure undergoing an evaluation ofendometrial response to oral cycle stimulation. Patients receivedincremental oral oestradiol valerate for varying durations atthe in-vitro fertilization unit of the Sheba Medical Center,Tel Hashomer, Israel. The treatment protocol involved the administrationof daily oestradiol valerate, starting with 1 mg/day, followedby a daily increment of 1 mg for a total of 4, 6 and 8 days.After the last day, a daily maintenance dose of 2 mg was continued.Serum oestradiol concentrations correlated with the dose oforal oestradiol valerate. Peak oestradiol concentrations (mean± SEM) were 572 ± 60, 721 ± 42 and 797± 53 pg/ml for 4, 6 and 8 days of oestradiol valerateadministration respectively. Serum LH, after an initial suppression,peaked 2 days after maximal oestradiol valerate dose and 1 dayafter peak serum oestradiol. The magnitude of the LH peak wasproportional to the duration of incremental oestradiol valeratetreatment. In conclusion, the LH surge is temporally relatedto the cessation of serum oestradiol increase. Consequently,the occurrence of this surge can be explained by a simple negativefeedback inhibition of pituitary LH release rather than by adual negative/positive mechanism.     

Quantification by magnetic resonance spectroscopy of metabolites in seminal plasma able to differentiate different forms of azoospermia

The aim was to determine whether proton magnetic resonance spectroscopy (1H-MRS) of metabolites such as glycerophosphorylcholine (GPC), choline, citrate and lactate in human seminal plasma can be used to differentiate (i) different azoospermic patients and (ii) different forms of spermatogenic failure including those who had undergone radiation therapy or chemotherapy. Semen samples were provided by men with obstructive azoospermia and spermatogenic failure who had serum follicle stimulating hormone (FSH) values within the normal range and either more or less than normal. Four prominent constituents of seminal plasma were identified by 1H-MRS: GPC, choline, citrate and lactate. The peak area ratios of choline/citrate as well as choline/lactate were significantly different (P < 0.01) between groups with spermatogenic failure and obstructive azoospermia. When the serum FSH values were normal in men with spermatogenic failure and obstructive azoospermia, a significant difference was found in the GPC/choline ratio (P < 0.001). When the FSH values were normal, the GPC/choline ratio appeared to be a very important parameter able to differentiate not only between cases of spermatogenic failure and obstructive azoospermia but also between different forms of spermatogenic failure. These results demonstrate the potential use of 1H-MRS on human seminal plasma in a new approach in the management of male infertility.