Dana A. Ohl

Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome

BACKGROUND Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. METHODS In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. RESULTS Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. CONCLUSIONS As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).

Total testosterone assays in women with polycystic ovary syndrome: Precision and correlation with hirsutism

CONTEXT There is no standardized assay of testosterone in women. Liquid chromatography mass spectrometry (LC/MS) has been proposed as the preferable assay by an Endocrine Society Position Statement. OBJECTIVE The aim was to compare assay results from a direct RIA with two LC/MS. DESIGN AND SETTING We conducted a blinded laboratory study including masked duplicate samples at three laboratories--two academic (University of Virginia, RIA; and Mayo Clinic, LC/MS) and one commercial (Quest, LC/MS). PARTICIPANTS AND INTERVENTIONS Baseline testosterone levels from 596 women with PCOS who participated in a large, multicenter, randomized controlled infertility trial performed at academic health centers in the United States were run by varying assays, and results were compared. MAIN OUTCOME MEASURE We measured assay precision and correlation and baseline Ferriman-Gallwey hirsutism scores. RESULTS Median testosterone levels were highest with RIA. The correlations between the blinded samples that were run in duplicate were comparable. The correlation coefficient (CC) between LC/MS at Quest and Mayo was 0.83 [95% confidence interval (CI), 0.80-0.85], between RIA and LC/MS at Mayo was 0.79 (95% CI, 0.76-0.82), and between RIA and LC/MS at Quest was 0.67 (95% CI, 0.63-0.72). Interassay variation was highest at the lower levels of total testosterone (≤50 ng/dl). The CC for Quest LC/MS was significantly different from those derived from the other assays. We found similar correlations between total testosterone levels and hirsutism score with the RIA (CC=0.24), LC/MS at Mayo (CC=0.15), or Quest (CC=0.17). CONCLUSIONS A testosterone RIA is comparable to LC/MS assays. There is significant variability between LC/MS assays and poor precision with all assays at low testosterone levels.

Sperm DNA damage in male infertility: etiologies, assays, and outcomes

Male factor infertility is the sole cause of infertility in approximately 20% of infertile couples, with an additional 30% to 40% secondary to both male and female factors. Current means of evaluation of male factor infertility remains routine semen analysis including seminal volume, pH, sperm concentration, motility, and morphology. However, approximately 15% of patients with male factor infertility have a normal semen analysis and a definitive diagnosis of male infertility often cannot be made as a result of routine semen analysis. Attention has focused on the role of sperm nuclear DNA integrity in male factor infertility. Here we review the structure of human sperm chromatin, the etiology and mechanisms of sperm DNA damage, current tests available to assess sperm DNA integrity, and effect of sperm DNA integrity on reproductive outcomes.

Electroejaculation versus vibratory stimulation in spinal cord injured men: sperm quality and patient preference.

PURPOSE We compared semen quality and patient preference between penile vibratory stimulation and electroejaculation in spinal cord injured men. MATERIALS AND METHODS We treated 11 spinal cord injured men with penile vibratory stimulation and electroejaculation in random order. End points examined were semen analysis, sperm functional assessment, and patient pain scores (1 to 10) and preferred procedure. Differences between the procedures were determined with the paired Student t test. RESULTS There was no difference in antegrade sperm count but penile vibratory stimulation specimens had greater motility (26.0 versus 10.7%), viability (25.2 versus 9.7%) and motile sperm count (185.0 x 10(6) versus 97.0 x 10(6)). The retrograde sperm count was greater (but not significant) in electroejaculation patients. The total (antegrade plus retrograde) and motile sperm counts were not different. There was no difference in immunobead test (all negative), cervical mucus penetration or sperm penetration assay, although the percent hamster egg penetration approached significance (53.7% for penile vibratory stimulation versus 22.1% for electroejaculation, p = 0.06). There was no difference in the peak blood pressures and no complications were noted. Pain scores were significantly greater for electroejaculation compared to penile vibratory stimulation (5.2 versus 1.7, respectively). All patients preferred penile vibratory stimulation. CONCLUSIONS There was a slight advantage in sperm quality and a high patient preference in favor of penile vibratory stimulation. Penile vibratory stimulation should be attempted first to induce ejaculation in spinal cord injured men, with electroejaculation reserved for failures.

Processed total motile sperm count correlates with pregnancy outcome after intrauterine insemination

OBJECTIVES To determine the impact of processed total motile sperm (PTMS) count on pregnancy after partner intrauterine insemination (IUI). IUI is generally attempted before proceeding to more expensive and invasive assisted-reproductive techniques such as intracytoplasmic sperm injection. Several semen parameters have been shown to correlate with IUI outcome and may be useful when counseling couples. METHODS Four hundred thirty-eight couples with diverse causes of infertility underwent 1114 cycles of husband IUI during a 39-month period. The clinical and semen parameters were recorded for each couple and each insemination. The parameters were compared between those couples who achieved a pregnancy and those who did not. RESULTS The total number of pregnancies was 120, resulting in a pregnancy rate per cycle of 10.8% and a couple pregnancy rate of 27.4%. On multivariable logistic regression analysis, the PTMS count was independently associated with fertility after IUI (P = 0.0014). Moreover, the pregnancy rate was significantly lower for couples with less than 10 million PTMS (P <0.05). CONCLUSIONS The results of this study have demonstrated that the PTMS count independently predicts success with IUI. Cycles with less than 10 million total motile sperm are significantly less likely to result in a pregnancy. If cause-specific therapy has failed, alternatives to IUI should be considered for couples when the PTMS count is less than 10 million.

The great debate: Varicocele treatment and impact on fertility

OBJECTIVE To evaluate the current literature on the impact and potential mechanisms of varicocele repair on male fertility. DESIGN Pertinent articles were identified through computer PubMed search on varicocele repair and male factor infertility. References of selected articles were hand searched for additional citations. CONCLUSION(S) Varicocele repair has been shown to reverse a spectrum of effects contributing to men with impaired fertility. Clinical studies on the intervention have illustrated variable effects on postoperative sperm parameters and pregnancy rates (PR). Studies with conflicting results suffer from a significant number of confounding variables such as variable repair technique or lack of controls. Additional studies are warranted on the role of modern microsurgical varicocelectomy given the improvements in assisted reproductive technologies (ART).

Electroejaculation and assisted reproductive technologies in the treatment of anejaculatory infertility

OBJECTIVE To determine the efficacy of electroejaculation in combination with assisted reproductive technology (ART). DESIGN Case series. SETTING University fertility program. PATIENT(S) One hundred twenty-one consecutive couples seeking treatment of anejaculatory infertility. INTERVENTION(S) Electroejaculation with IUI, or gamete intrafallopian transfer or IVF. MAIN OUTCOME MEASURE(S) Pregnancy and pregnancy outcome. RESULT(S) Fifty-two couples became pregnant (43%), 39 by IUI alone (32.2%). Cycle fecundity for IUI was 8.7%. No difference in cycle fecundity was seen among ovarian stimulation protocols (clomiphene citrate, 7.6%, hMG, 13.2%, and natural cycle, 11.2%). Pregnancy was unlikely when the inseminated motile sperm count was <4 million. Female management protocol and etiology of anejaculation did not affect results. Patients undergoing IVF had higher cycle fecundity (37.2%) than did those undergoing IUI. The rates of spontaneous abortion and multiple gestations were 23% and 12%, respectively. CONCLUSION(S) Electroejaculation with stepwise application of ART is effective in treating anejaculatory infertility. Intrauterine insemination with the least expensive monitoring protocol should be used for most couples, because use of more expensive monitoring did not improve results. It is cost-effective to bypass IUI and proceed directly to IVF in men who require anesthesia for electroejaculation and in those with a total inseminated motile sperm count < 4 million.

Treatment of infertility in men with spinal cord injury

Most men with spinal cord injury (SCI) are infertile. Erectile dysfunction, ejaculatory dysfunction and semen abnormalities contribute to the problem. Treatments for erectile dysfunction include phosphodiesterase type 5 inhibitors, intracavernous injections of alprostadil, penile prostheses, and vacuum constriction devices. In anejaculatory patients who wish to father children, semen retrieval is necessary. Penile vibratory stimulation is recommended as the first line of treatment. Patients who fail penile vibratory stimulation can be referred for electroejaculation. If this approach is not possible, prostate massage is an alternative. Surgical sperm retrieval should be considered as a last resort when other methods fail. Most men with SCI have a unique semen profile characterized by normal sperm count but abnormally low sperm motility. Scientific investigations indicate that accessory gland dysfunction and abnormal semen constituents contribute to the problem. Despite abnormalities, sperm from men with SCI can successfully induce pregnancy. In selected couples, the simple method of intravaginal insemination is a viable option. Another option is intrauterine insemination. The efficacy of intrauterine insemination increases as the total motile sperm count inseminated increases. In vitro fertilization and intracytoplasmic sperm injection are options in cases of extremely low total motile sperm count. Reproductive outcomes for SCI male factor infertility are similar to outcomes for general male factor infertility.

Penile rehabilitation after radical prostatectomy: what the evidence really says

The pathophysiology of erectile dysfunction after radical prostatectomy (RP) is believed to include neuropraxia, which leads to temporarily reduced oxygenation and subsequent structural changes in penile tissue. This results in veno‐occlusive dysfunction, therefore, penile rehabilitation programmes focus on tissue oxygenation. Animal studies support the use of phosphodiesterase type 5 inhibitors (PDE5Is) after cavernous nerve damage but results from human studies are contradictory. The largest study to date found no long‐term effect of either daily or on‐demand PDE5I administration after RP compared with placebo. The effects of prostaglandin and vacuum erection devices are questionable and high‐quality studies are lacking. Better documentation for current penile rehabilitation and/or better rehabilitation protocols are needed. One must be careful not to repeat the statement that penile rehabilitation improves erectile function after RP so many times that it becomes a truth even without the proper scientific backing.

Vacuum erection device in spinal cord injured men: Patient and partner satisfaction

OBJECTIVE To assess the efficacy of and patient and partner satisfaction with a vacuum erection device (VED) to treat erectile dysfunction of spinal cord injury. DESIGN Case series. SETTING University hospital outpatient clinic. PATIENTS Twenty spinal cord injured men with erectile dysfunction and their heterosexual partners, recruited from outpatient population and by advertisement. INTERVENTION Use of a VED to obtain erections for sexual activity. MAIN OUTCOME MEASURES Efficacy in obtaining adequate penile erection, and patient and partner satisfaction with the device (survey). RESULTS At 3 months, 93% of the men and 83% of the women reported rigidity sufficient for vaginal penetration, with an average duration of 18 minutes. These numbers decreased somewhat at the 6-month control. At 6 months, 41% of the men and 45% of the women were satisfied with the device, with premature loss of rigidity during intercourse the most commonly reported complaint. Sixty percent of men and 42% of women indicated an improvement of the sexual relationship. Minor side effects, such as petechiae and penile skin edema, occurred frequently, but there were no complications that required treatment. CONCLUSION The VED is effective in many couples in the treatment of erectile dysfunction associated with spinal cord injury. The devices were not universally accepted, but had a significant impact on sexual activity and sexual satisfaction for nearly half the couples. Vacuum erection devices should be presented to SCI men along with other options for treatment of erectile dysfunction.