An empiric treatment for idiopathic oligozoospermia revisited: a 20-year investigative saga.

A series of studies aiming at introducing an effective treatment for idiopathic oligozoospermia was conducted in a step-wise fashion spanning over a 20-year period. The concept was that co-administration of an accessory gland-stimulating androgen, testosterone undecanoate (40 mg t.i.d.) and the FSH raising anti-oestrogen tamoxifen citrate (10 mg b.i.d.) may improve sperm parameters. A prerequisite for such an effect was the demonstration that testosterone undecanoate had no suppressing action on pituitary-testicular axis. In this context, initial studies demonstrated no change in basal or stimulated gonadotrophin and testosterone secretion in short- or long-term protocols. Two subsequent trials with this combination showed a marked improvement of sperm parameters and pregnancy incidence, with a seasonal variation noted in response to treatment, this being higher during the cold seasons of autumn and winter. Regarding the mechanism of testosterone undecanoate's action, a recent study from our unit showed that its administration resulted in a marked rise of serum DHT levels. Because this steroid is an epididymal function promoter, it appears that its contribution in the combination is mediated mainly through its DHT raising effect. By and large, this empiric approach for the treatment of idiopathic oligozoospermia was satisfactorily documented after a 20-year investigative saga.

'Value of FSH and inhibin-B measurements in the diagnosis of azoospermia'--a clinician's overview.

Azoospermia can be either of obstructive ctiology or due to the testis' failure to initiate or maintain spermatogenesis. FSH acts through its receptor at Sertoli cell level and modulates spermatogenesis initiation and maintenance. Inhibin B is a Sertoli cell product expressing the functional capacity of the cell and in an indirect way the state of seminiferous tubule activity. Both FSH and inhibin B differentiate clearly testicular from extra-testicular pathology of azoospermia while, none of these hormones has been convincingly established as predictory index for the finding of spermatozoa in TESE.

Seasonality in sperm parameters in normal men and dyspermic patients on medical intervention.

This study attempted to investigate the presence of seasonal variations in sperm parameters and to evaluate the season's impact on the response to treatment in men with idiopathic oligozoospermia (IO). To this end, a retrospective analysis of the records of 294 men, who participated in a controlled study, was performed. This sample included IO men (n = 106) treated with tamoxifen citrate (10 mg b.i.d.) and testosterone undecanoate (40 mg t.i.d.) or placebo (n = 106) and normozoospermic men (n = 82) serving as controls. Outcome measures included sperm parameters, functional sperm fraction (FSF) and incidence of pregnancy. Analysis showed a raised frequency of high FSF values and increased area under the response curve (AURC) for FSF mean during autumn-winter seasons in patients on active treatment compared with those in placebo (P < 0.05-P < 0.04). Moreover, receiver operation characteristics (ROC) curves for a >100% FSF rise significantly discriminated autumn-winter from other seasons (P < 0.001, all), whereas active treatment showed higher than placebo FSF values particularly during autumn and winter (P < 0.001, all). The pregnancy incidence was higher in the autumn in all groups. It is concluded that FSF values showed a better response to active treatment during autumn and winter, indicating that commencement of empirical treatment at this time in IO men may stand a better chance to succeed.

The combination of testosterone undecanoate with tamoxifen citrate enhances the effects of each agent given independently on seminal parameters in men with idiopathic oligozoospermia.

OBJECTIVE: To evaluate the effects of combined tamoxifen citrate and T undecanoate treatment on seminal parameters in men with idiopathic oligozoospermia. DESIGN: Prospective randomized clinical study. SETTING: A state hospital tertiary clinic. PATIENT(S): Eighty oligozoospermic men were included in the protocol. INTERVENTION(S): Patients were randomized to receive placebo, T undecanoate (40 mg three times per day), tamoxifen citrate (10 mg two times per day), or T undecanoate plus tamoxifen citrate. RESULT(S): Tamoxifen citrate plus T undecanoate treatment produced a satisfactory improvement of total sperm number, motility, and functional sperm fraction after 3 and 6 months. Comparisons with other active treatment groups showed significantly higher increment values for motility and functional fraction, whereas aniline, acrosine, and free L-carnitine also were markedly better in the combination treatment group. CONCLUSION(S): These results indicate that the combination of tamoxifen citrate with T undecanoate not only improves significantly important seminal parameters but also compares favorably with the single treatments used. Therefore, this combination deserves a place as a first line of treatment in idiopathic oligozoospermia.

Testicular secretion after pulsatile human menopausal gonadotropin therapy in gonadotropin-releasing hormone agonist desensitized dysspermic men.

OBJECTIVE: To evaluate Leydig and Sertoli cell response to prolonged pulsatile stimulation with hMG after pituitary desensitization with the GnRH agonist (GnRH-a) triptoreline in normogonadotropic men with abnormal semen analyses. DESIGN: A group of four oligozoospermic men were investigated in the following manner: [1] basal and GnRH-hCG stimulated activity were assessed in all volunteers; [2] a long-acting form of the GnRH-a triptoreline (3.75 mg every month for 3 months) was given, and its effectiveness was evaluated on day 20; and [3] on that day hMG pulsatile administration was introduced (150 IU per 24 hours in 90-minute pulses) with serial hourly sampling (6 to 7 hours) for measurement of FSH, LH, T, E2, and inhibin on days 20, 41, and 90 from the first GnRH-a injection. RESULTS: Initial evaluation showed normal basal, GnRH, and hCG-stimulated hormone concentrations. Pituitary and gonadal activity were effectively suppressed by GnRH-a when tested on day 20. Pulsatile hMG had no immediate stimulatory effect on gonadal activity (day 20). However, on middle and final evaluations (days 41 and 90), basal T, E2, and inhibin had risen to pre-GnRH-a levels, and, moreover, distinct secretory pulses were seen for these hormones. CONCLUSION: These findings indicate that suppression of pituitary gonadotropin activity with triptoreline combined with pulsatile hMG stimulation offers a new, useful tool for investigation of the male reproductive system in oligozoospermic men.

Raised sodium, potassium, and urea concentrations in spermatic venous blood: an additional causative factor in the testicular dysfunction of varicocele?

The concentrations of Na, K, Cl, HCO3, LA, and urea, with calculation of the AG, as indirect indices of electrolyte balance and metabolic conditions prevailing in testicular environment, were determined in PB and SVB of 24 men with varicocele and 15 men with inguinal hernia. Significantly higher concentrations of Na, K, and urea were found in SVB as compared with PB values (P less than 0.001 for all) of patients with varicocele, but not in control subjects. The SVB concentrations of Na, K, and urea in varicocele patients were higher than SVB and PB concentrations of the control group (P less than 0.001 for all). It is concluded that urea, Na, and K concentrations are raised in SVB of patients with varicocele; this imbalance may be related, among other factors, to the pathogenesis of dyspermia in varicocele.

Endocrine effects of testosterone undecanoate as a supplementary treatment to menopausal gonadotropins or tamoxifen citrate in idiopathic oligozoospermia.

OBJECTIVE: To evaluate the effects of T undecanoate given as a supplementary treatment with tamoxifen citrate (TAM) or hMG on pituitary and Leydig cell function in men with idiopathic oligozoospermia. DESIGN: A total of 48 normogonadotropic men with idiopathic oligozoospermia were allocated in to six groups (n = 8 per group) treated with placebo, 40 mg T undecanoate three times per day, 10 mg TAM two times per day, T undecanoate and TAM, 75 IU/d hMG, and T undecanoate and hMG. All groups were evaluated with standard GnRH, thyrotropin-releasing hormone, and hCG tests before and on the final day of 3 months on treatment with measurements of FSH, LH, thyroid-stimulating hormone (TSH), PRL, T, E2, 17-hydroxyprogesterone, sex hormone-binding globulin, and seminal analyses (at least twice each time). RESULTS: Basal and stimulated concentrations and incremental FSH and LH values showed no differences among TAM or hMG and TAM + T undecanoate or hMG + T undecanoate treated groups. Basal, stimulated, and incremental values for TSH and PRL were elevated markedly during treatment in most groups in comparison to placebo. Basal, stimulated, and incremental T and E2 values were similar in active treatment groups except that higher T concentration was found in TAM + T undecanoate as compared with T undecanoate only treated men. Finally, significant improvements were noted in important seminal parameters and particularly in the functional sperm fraction of the TAM + T undecanoate group as compared with single treatment with TAM. CONCLUSION: These results indicate that T undecanoate in combination with TAM or hMG not only had no adverse effects on pituitary and Leydig cell activity but also seemed to improve important seminal parameters and signify that androgens may be tried as a supplementary treatment to conventional regimes in idiopathic oligozoospermia.

Sex steroids in cervical mucus of spontaneous or induced ovulatory cycles.

Evaluation of sex steroids in cervical mucus was performed at different phases of spontaneous or clomiphene-citrate-induced ovulatory cycles. To this end, 11 women with normal ovulatory cycles and 9 subjects with polycystic ovary syndrome of comparable age and body mass index were investigated. Serum and cervical mucus samplings were assessed for 17beta-estradiol (E2), progesterone, testosterone, and sex hormone binding globulin levels at the pre-, peri-ovulatory, and mid-luteal phases of the cycle. The cervical mucus maturation index also was estimated in all women. Measurable amounts of E2 were found in most mucus samples with a cyclic variation in all cases. The highest E2 and mucus maturation index values coincided, but both lagged by 24 h behind the serum mid-cycle peak of this steroid. Detectable amounts of progesterone were found in the luteal phase, testosterone was present at low levels throughout the cycle, but sex hormone binding globulin was undetectable in all cervical mucus samples. Differences between spontaneous or drug-induced ovulatory cycles were not found. It is concluded that sex steroids are present in human cervical mucus, showing variations similar to those in peripheral blood. The significance of these findings is not clear at present, but it is probably related to the cyclic changes of cervical epithelium and gland secretion. An important implication of the absence of measurable sex hormone binding globulin amounts in cervical mucus is that the free fraction of sex steroids present in that fluid are presumably higher, and therefore, expected to exert greater biologic activity than in peripheral blood.

The incidence of positive oestrogen and progesterone receptors in breast cancer of Greek women.

Oestrogen and progesterone receptors were determined in breast tumours of 80 Greek women. Oestrogen-positive receptors were found in 84.6% of the pre (n = 39) and 85.4% of the postmenopausal (n = 41) patients while progesterone-positive receptors were found in 71.8% of these women respectively. In combination, 69.2% of the pre-menopausal had both receptors detectable, 15.4% had oestrogen-positive and progesterone-negative and 2.6% had oestrogen negative and progesterone-positive while 12.8 had no detectable receptors. This incidence in postmenopausal women was 51.2, 34.2, 0.0, 14.6% respectively. The ratio of progesterone to oestradiol receptor concentration was 7.6 in the pre- and 1.7 in the postmenopausal group (p less than 0.05). In conclusion, the incidence of positive receptors in Greek women with breast cancer is similar to that of other Western populations.

Medical treatment of idiopathic oligozoospermia and male factor subfertility.

Pharmaceutical treatment for the so-called idiopathic oligozoospermia (I. O.) is possible and effective in a fair proportion of patients with the syndrome provided that appropriate investigative procedures may identify the major disorder or its level of disruption, this abnormality is reversible and appropriate prognostic indices for the treatment's success are devised and validated. According to the evidence available, minimal evaluation and prognostic indices for treatment eligibility in normogonadotropic men with I. O. include a routine work-up but, mainly, microscopical assessment of spermatogenesis and appraisal of Sertoli cell's functional capacity. Published data indicate that men with hypospermatogenesis without maturational arrest, respond favorably to agents stimulating Sertoli cells and germinal epithelium with increased sperm production. Furthermore, Sertoli cell activity as judged by cell-specific indices such as inhibin B secretion, may provide additional discriminating power to the microscopical picture of the testis. In this context, precise identification of the causative factor(s), together with the establishment of prognostic indices are the most important criteria on which the decision, for or against medical treatment in I. O., should be based. Obviously, further basic research and clinical trials are urgently needed in this particular field, and this should be a major task for clinical andrologists.

Gastrin secretion in the menstrual cycle and pregnancy.

Gastrin (1--17) concentration was estimated under basal conditions in 12 menstruating women, and 42 women with normal pregnancy. In 10 women with normal pregnancy this hormone was also measured 10 days after delivery. In addition, gastrin was determined after stimulation with a standard protein meal in 7 menstruating women, 12 women with normal pregnancy and 14 women with complicated pregnancies. Umbilical vein blood levels of gastrin were also determined in 5 cases while, in 3 women serial hormone estimations were carried out for 24 hours after normal delivery. The mean (+/- SEM) basal gastrin concentration was 36.1 +/- 2.9 pg/ml in the productive and 45.4 +/- 2.0 in the secretory phase of the cycle (p less than 0.02). The mean basal concentration in normal pregnancy (60.4 +/- 5.4) was higher than that of the normal cycle as a whole (p less than 0.001), showed no significant variations related to the progress of pregnancy, and fell to normal cycle levels after delivery (42.1 +/- 2.9). In complicated pregnancies the mean hormone concentration (47.0 +/- 2.3) was lower than that of normal pregnancies (p less than 0.05) and similar to that of the secretory phase of the cycle. Gastrin responses to protein meal were similar in all 3 groups studied, with maximal concentration at 30 min, and a gradual decline thereafter. Umbilical vein blood levels of gastrin were generally higher than in maternal circulation but not significantly so. Serial estimations of gastrin after delivery failed to show any uniform pattern of changes. It is concluded that variations of gastrin secretion related to the phase of the menstrual cycle or the reproductive state may occur in women.

Endocrinological studies in two patients with post contraceptive cyclic dysfunction.

PIP: Serial assays of urinary estrogens, pregnanediol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), WERE PERFORMED IN 2 NORMAL women who developed amenorrhea as a result of oral contraceptive use. Case 1, a woman aged 28 with 2 children took Ovulen (mestranol .1 mg and ethynodiol diacetate 1.0 mg) for 25 months followed by a substitution of chlormadinone acetate (.5 mg per day) when she developed increased menstrual irregularity. Following withdrawal of the medication, vaginal bleeding began and lasted 4 days, and she experienced regular cycles for the subsequent 2 years. The second woman aged 21 developed amenorrhea after 17 months' use of Gynovlar (ethinyl estradiol .05 mg and norethistrone acetate 3.0 mg). Amenorrheic for 21 months at the time of investigation, she was given clomiphene citrate for 5 days (50 mg/day). Further treatment with clomiphene and Pergonal (Serono-Rome) was necessary to resume normal cycles and permit conception which led to full term delivery. Estrogen levels were similar to those of the follicular phase of the normal menstrual cycle; however, they rose spontaneously to midcycle levels in case 1 and as a result of clomiphene treatment in case 2. FSH levels were normal but failed to show consistent patterns; LH patterns were highly irregular in both cases. The findings are consistent with the hypothesis that longterm therapy by oral contraceptives may cause irregular cyclic release of gonadotrophins at the hypothalamic level resulting in amenorrhea and anovulation.^ieng

Do lunar phases influence menstruation? A year-long retrospective study.

We assessed with cross-approximate entropy menstruation onset versus moon phases in 74 women with 980 menstrual cycles over a calendar year. In defiance of traditional beliefs and contrary to what some researchers have argued with short-term research work, in this long-term study we did not find any synchrony of lunar phases with the menstrual cycle.

Present and future therapeutic strategies for idiopathic oligozoospermia.

The effectiveness of medical treatment for idiopathic oligozoospermia (IO) has been at best doubtful until now and a logical consequence of this unsatisfactory situation has been the partial displacement of this approach by assisted reproduction techniques. This state of affairs has resulted from insufficient investigation, inappropriately designed clinical trials and consistent disregard for the principles of evidence-based medicine. Protocol-related shortcomings and wrong interpretation of the data available have also been some of the all too frequent problems encountered in this therapeutic approach. In this rather misty situation, it appears that, of the therapeutic agents used so far, follicle stimulating hormone (FSH) (mainly FSH-secretagogues) may exert some beneficial effects on a number of biological endpoints related to spermatogenesis and sperm maturation. The short and medium term prospects of medical treatment for IO rest mainly with improvement of investigative procedures to a higher degree of sophistication, with emphasis placed on identifying the causes rather than the results of dysfunction so that a better selection of candidates can be made. Moreover, the introduction of prognostic indices for evaluation of the beneficial effects of a therapeutic agent may be of paramount importance. Finally, a better assessment of the preparations available and, possibly, the introduction of new more specific agents may also be an important step forward in this field. This type of large-scale effort should not be left to individual investigators or special centres working independently, but it may come under the auspices of a central regulating agency so that undisputed results from large, multicentre and uniform studies might be obtained, if medical treatment is to remain a good option. In this context, it may also be emphasized that andrology's main task should always be to treat the male with the problem rather than his healthy female partner, whenever this is possible.

Prolactin concentration in milk and plasma of puerperal women and patients with galactorrhea.

Prolactin (PRL) concentration was estimated in milk and blood of women with various types of galactorrhea (n = 53) and was compared with lactating (n = 17) and normally menstruating women (n = 36). Mean milk (+/- SD) PRL concentration in lactating women (160 +/- 66 micrograms/l) was similar to that of galactorrhea due to pituitary adenoma (149 +/- 87 micrograms/l, n = 24), thyroid dysfunction (193 +/- 72 micrograms/l, n = 8), functional causes (192 +/- 91 micrograms/l, n = 10) or recent pregnancy (198 +/- 44 micrograms/l, n = 2), but higher than that of sex steroid-induced galactorrhea (85 +/- 53 micrograms/l, n = 9). Plasma PRL concentration in lactating women (208 +/- 102 micrograms/l) was higher than in normal control women (14 +/- 5 micrograms/l) and patients with galactorrhea due to thyroid dysfunction (36 +/- 15 micrograms/l), functional causes (16 +/- 8 micrograms/l), drugs (20 +/- 4 micrograms/l), recent pregnancy (22 +/- 3 micrograms/l) or pituitary adenoma (145 +/- 53 micrograms/l). The milk to plasma PRL concentration ratio was 0.8 +/- 0.4 in lactating women and 1.1 +/- 0.7 in patients with adenoma but significantly higher (p = 99% two-sided) in galactorrhea due to thyroid dysfunction (4.4 +/- 2.1), drugs (3.4 +/- 1.1) or functional causes (12.3 +/- 4.3). Bromocriptine administration reduced PRL in both fluids. It is concluded that in women with galactorrhea milk PRL concentration is similar to that of nursing mothers, but plasma levels of this hormone are significantly lower than that of the latter group in all but the pituitary adenoma related galactorrheas.