How to evaluate the azoospermic male? ASRM committee recommendations

The Practice Committee of the American Society for Reproductive Medicine (ASRM) in collaboration with the Society for Male Reproduction and Urology recently issued guidelines about the diagnosis and evaluation of the azoospermic male partner. The committee opinion was published recently in journal Fertility and Sterility.

Of all the infertility cases about 30% is because of ‘male-factor’ of whom about 10-15% of men will receive the diagnosis of azoospermia. Recent studies have documented a decline in sperm count globally with a concurrent increase in male factor infertility.

Azoospermia is classified into 3 categories-pre-testicular, testicular, and post-testicular according to the etiology but in clinical practice, azoospermia is commonly classified as obstructive azoospermia (OA) and nonobstructive azoospermia (NOA) which can be of central or testicular origin. 

 

Azoospermic men with normal size testes with normal serum follicle-stimulating hormone (FSH) levels are more likely to have obstructive azoospermia, while men with a significant elevation in FSH have a testicular failure, and thus testicular NOA.

On the other hand, low gonadotropins levels with low to low-normal T points towards a diagnosis of central NOA.

According to the American Society for Reproductive Medicine (ASRM) Practice Committee, the evaluation begins with a standard reproductive history and physical examination, followed by measurement of serum FSH and testosterone(T), luteinizing hormone (LH), free T, estradiol, and prolactin. Most experts state that an FSH >7.6 mIU/mL would be considered abnormal.

Semen volume and FSH levels play an essential part in determining the etiology of azoospermia. If men have low semen volume and normal FSH the lab test should be repeated after 2-3 days of abstinence, with attention to proper collection technique. A post-ejaculate urinalysis is advised to rule out retrograde ejaculation. If there is no retrograde ejaculation and semen pH is < 7.2, a transrectal ultrasound (TRUS) is the next step to identify a possible ejaculatory duct obstruction (EDO).

In men with normal semen volume, determining serum FSH and testicular volume is critical to decide in favor of testicular biopsy for the prognostic purpose. Elevation of serum FSH along with low testicular volume strongly suggests NOA. In case sperm retrieval is planned for ICSI, the testicular biopsy is deferred till the sperm retrieval when a biopsy sample is concurrently sent to the lab.

A normal testicular biopsy indicates an obstruction at some level in the reproductive tract. If the cause of OA is not iatrogenic, then the cause is a bilateral epididymal obstruction. It should be confirmed by surgical exploration. Vasography is only indicated if reconstructive surgery is planned simultaneously.

In men with the congenital bilateral absence of the vasa deferentia (CBAVD or vasal agenesis), unilateral renal agenesis should be ruled out. Most men with vasal agenesis will also have seminal vesicle hypoplasia or agenesis which manifests as low semen volume and pH.

CBAVD is also strongly associated with mutations of the CFTR gene. Hence, before planning a sperm retrieval for ICSI in men with CBAVD or congenital unilateral absence of the vas deferens (CUAVD), genetic testing should be offered to female partner to rule out her carrier status (∼4%) for CFTR gene.

Men with suspected NOA due to an elevated FSH and a normal ejaculate volume have bilateral testicular atrophy.  They should be offered genetic testing to exclude chromosomal abnormalities and Y-chromosome microdeletions (YCMD). A diagnostic testicular biopsy is not usually indicated in such cases. 

Low gonadotropins levels may be because of feedback inhibition secondary to exogenous T or illicit anabolic-androgenic steroid use, a high T level with suppressed gonadotropins will be confirmatory in such instances.

In men with markedly elevated serum FSH levels, the diagnostic testicular biopsy is only indicated when there is uncertainty about the etiology of the azoospermia- obstructive or nonobstructive. In all other cases, a testicular biopsy is done when sperm retrieval is planned for ICSI.

A diagnostic biopsy is also not necessary in patients with expected obstruction and normal FSH levels.

Full-text Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction and Urology

Ob/Gyn Updated Facebook page

Is the age at natural menopause predictable using Ovarian Reserve Tests or Mother's Age at Menopause? A systemic review.

The first signs of aging are ineludible. The decrease of ovarian function is an important turning point in a woman’s life. But, with current increase in life expectancy women will be expected to live one-third of there lives in this hormone deficient stage.

The average age at final menstruation period (FMP) is 51 years, but menopause occurs between 40-60 years. There is discrepancy between the ability to maintain a normal ovulatory cycle and actual cessation of fertility potential, which is largely  controlled by a set of genes. These genes carry heritable variants, modifying the wide range of ovarian and reproductive aging seen in population based studies.  But, there is a fixed interval of 10 years between the end of fertility and the natural menopause.

 

In recent years we have seen an increase in age- related infertility in women because of postponement of childbirth due to career choices, education, control over fertility, financial concerns, late and second marriages, and infertility.  So, researchers are looking for markers which can accurately predict the end of fertility life span, limiting the number of women unknowingly facing age related infertility. This prediction could also help in timely planning the family or cryopreservation, and decreasing involuntary childlessness.

Currently, no marker has been yet identified that can accurately predict the end of human fertility, hence the final menstrual period is taken as a proxy variable to signify the end of fecundity. Personalized forecast regarding the approximate age at menopause is usually predicted based on age in relation to regularity of cycles.

According to the stages of Reproductive Aging Workshop (STRAW) FSH is very accurate in determining the current state of reproductive aging, but it does not predict the timing of final menstrual period (FMP). Similarly other parameters of Ovarian reserve tests such as antimüllerian hormone (AMH) and antral follicle count (AFC) and levels of inhibin-B lack standardized assays limiting their incorporation and utility as clinical tools for staging reproductive aging.

Researchers also turned towards identifying genetic markers responsible predicting age at natural menopause, but despite identifying potential genetic loci, no dominant alleles responsible for ovarian depletion have been discovered to date. Mother’s age at menopause seems promising to the researchers as it has demonstrated high degree of heritability. Pedigree analysis has shown a dominant pattern of inheritance of natural menopause.

This systemic review was published in February issue of Journal Menopause, aims to evaluate data on prediction of age at natural menopause based on antimüllerian hormone (AMH), antral follicle count (AFC), and mother's ANM so as to use in clinical practice and future research.

The authors conducted three searches and systemic review and included studies up to September 2014, which met the inclusion criteria.

.

Six studies were selected for AMH, out of which 5 were prospective studies and 1 was cross sectional study. These studies had limitations as the levels of AMH were determined by three different assays, and different laboratories making pooling of data impossible. Furthermore, smoking affects the levels of AMH and most of the studies did not correct for it.

For correlating the AFC and predicting age at natural menopause 2 studies were found that met the criteria. AFC measurement was performed on cycle days 2 to 4. It was seen that although in univariate regression AFC showed be promising predictor, when corrected for age and smoking the results were statistically non significant (P=0.13)

Mothers’s ANM is a promising variable in predicting ANM, studies of mother’s ANM consistently stated that among women who had early menopause, their mothers or daughters are highly likely to have early menopause. Daughters of mothers with early menopause also have low levels of AMH and low follicular count.

The studies included have many limitations as only including women with regular cycles, dominance of studies with women of  particular ethnicity,  lack of  including women taking external hormones  and  women with chronic illnesses, such as malignant diseases, genetic diseases, and autoimmune diseases.

The main rationale for predicting ANM is to prevent unwanted childlessness, knowledge of which would encourage women to start family early or to timely cryopreserve eggs.

Knowing mother's age at menopause may be pivotal information for the daughter. Further implications of knowing the ANM will also help in earlier treatment of bone loss and CVDs.

This systematic literature review is the first to use variables AMH, AFC, and mother's ANM in predicting menopause. This review has shown that AMH and mother’s ANM are the most promising variables to be used in daily clinical practice. The models used to predict ANM lack precision at both end of the spectrum and provide wide intervals. A single reading is not capable of predicting the exact age. A large cohort of women with variable age, corrected for smoking and other chronic diseases are followed for a long time with repeated measurements for   AMH and AFC and incorporating mother ANM than a firm conclusion can be drawn. However, all these markers need further research and improvement before they can be applied into day to day clinical practice. At present mother’s ANM seems to be most promising for future research.

References:

http://www.ncbi.nlm.nih.gov/pubmed/8582512

http://www.medscape.com/viewarticle/858678

http://www.ncbi.nlm.nih.gov/pubmed/12099629

http://www.ncbi.nlm.nih.gov/pubmed/9922101

http://www.ncbi.nlm.nih.gov/pubmed/9871906

http://www.ncbi.nlm.nih.gov/pubmed/3536609

http://depts.washington.edu/endolab/Publications_2012/Harlow_etal_2012.pdf

http://www.reproductivefacts.org/uploadedFiles/ASRM_Content/News_and_Publications/Journals_and_Newsletters/Menopausal_Medicine/2011/MenMed_0511.pdf

http://newsroom.ucla.edu/releases/researchers-find-a-way-to-predict-244164