UT5 - Andrologia (2)

Question 1

Infertility?

Answer 1

❑ Infertility is the inability of a sexually active, non-contracepting couple to achieve spontaneous pregnancy in one year
❑ Entails social, economic, psychological, and physical impact
❑ The ability to have children represents more than a quality-of-life issue
❑ The World Health Organization (WHO) has defined infertility as a disease

Question 2

Infertility - Epidemiology?

Answer 2

❑ 15% of couples do not achieve pregnancy within 1 year
❑ Almost 50% of them do so spontaneously in the second year, and another 14% in the third year – resolved infertility
❑ <5% remain childless
❑ 1/8 couples – primary infertility
❑ 1/6 couples – secondary infertility

Question 3

Male Factor Infertility Causes?

Answer 3

❑ Em 30 % dos casos de infertilidade masculina não é identificada a causa.
❑ Nestes casos, pensa-se que há uma disrupção endócrina associada à poluição ambiental, exposição de radicais livres de oxigénio e anomalias epigenéticas.
❑ Nos restantes 70 % encontram-se causas como anomalias urogenitais adquiridas ou congénitas, neoplasias, infeções do trato genito-urinário, aumento da temperatura escrotal (como ocorre no varicocelo), distúrbios endócrinos, anomalias genéticas ou alterações imunológicas.

Question 4

Male Factor Infertility Causes - Categories?

Answer 4

❑ Male factor infertility may be divided into 4 categories:
1. Pre-testicular (typically defects of the hypothalamic-pituitary-gonadal axis)
2. Testicular (either intrinsic defects or interference with testicular function by extragonadal or extrinsic factors)
3. Post-testicular (obstruction, sexual dysfunction)
4. Idiopathic

Question 5

Infertility - Recommendations?

Answer 5

❑ Investigate both partners simultaneously, to categorize infertility
❑ Examine all men diagnosed with fertility problems, including men with abnormal semen parameters for urogenital abnormalities

Question 6

Main prognostic factors in infertility?

Answer 6

❑ Age and fertility status of the female partner
❑ Duration of infertility
❑ Primary or secondary infertility
❑ Results of semen analysis (espermograma)

❑ Female age and the associated decline in ovarian reserve is the most important single variable influencing outcome in both spontaneous and assisted reproduction; por exemplo, comparando com uma mulher de 25 anos, o potencial de fertilidade numa mulher de 35 anos é de 50%, numa de 38 anos é de 25% e com mais de 40 anos é de menos de 5%.
❑ Numa sociedade em que as mulheres têm filhos cada vez mais tarde, este é um fator muito relevante.

Question 7

General fertility history?

Answer 7

❑ Time the couple has been deliberately trying to conceive
❑ Time the couple has been engaging in unprotected intercourse
❑ The frequency and timing of vaginal intercourse (female partner’s menstrual cycle)
❑ Previous pregnancy either together or with a prior partner
❑ Interventions and treatments that have been attempted before

Question 8

Medical conditions?

Answer 8

❑ Genetic diseases (Klinefelter syndrome, cystic fibrosis)
❑ Chronic conditions (systemic inflammation) – a inflamação crónica afeta a espermatogénese
❑ Neuropathic / neurologic conditions (diabetes, spinal cord injuries) – afetam ejaculação
❑ Hyperthyroidism and hypothyroidism

Question 9

Lifestyle factors?

Answer 9

Podem afetar a espermatogénese
❑ Physical exercise
❑ Diet factors
❑ Stress
❑ Smoking

Question 10

Medications?

Answer 10

❑ Exogenous testosterone; abuse of anabolic steroids – afetam o eixo hipotálamo-hipófise-gonadal
❑ 5-alpha reductase inhibitors (finasteride and dutasteride) – usados no tratamento da alopécia em homens jovens; estes medicamentos causam diminuição do volume de esperma
❑ Drugs associated with impairment of spermatogenesis (nitrofurantoin, cimetidine, sulfasalazine, spironolactone, colchicine, valproate, calcium channel blockers, lithium, chemotherapeutic agents, and antimetabolites)
❑ Drugs that may interfere with emission or ejaculation – antidepressants (selective serotonin reuptake inhibitors and tricyclics), antipsychotic agents, and alpha-blockers (estes últimos causam ejaculação retrógada)

Question 11

Infection/inflammation?

Answer 11

❑ Fever has a suppressive effect on spermatogenesis
❑ History of urethritis / prostactitis (typically from sexually transmitted infections) may suggest obstructive causes
❑ Mumps (papeira) may lead to severe viric orchitis that can impair spermatogenesis
❑ Men with recurrent sinus infections or bronchitis and low sperm motility may have immotile cilia syndrome
❑ A espermatogénese tem um ciclo de 60-90 dias, pelo que as sequelas de uma doença / infeção / inflamação sistémica podem não ser imediatas no espermograma!

Question 12

Surgery?

Answer 12

❑ History of orchidopexy, scrotal surgery or inguinal hernia surgery (resultando em lesões do canal deferente, na artéria testicular com eventual atrofia testicular etc)
❑ History of orchidectomy for torsion, cancer or trauma
❑ Transurethral resection of the prostate may cause retrograde ejaculation
❑ Retroperitoneal lymph node dissection for testicular tumors may disrupt the sympathetic chain ganglia, leading to failure of seminal emission before ejaculation

Question 13

Developmental abnormalities?

Answer 13

❑ Abnormalities of pubertal development
✔ Klinefelter syndrome (karyotype 47, XXY; often associated with tall stature, gynecomastia and small testes; hypergonadotropic hypogonadism)
✔ Kallmann syndrome (anosmia, small testes; hypogonadotropic hypogonadism)
❑ A history of hypospadias and/or undescended testicle(s) (criptorquidia) is also suggestive of potential hormonal or spermatogenic defects – associam-se a disgenesia testicular

Question 14

Other aspects of the history?

Answer 14

❑ Toxic/environmental exposure
* History of recurrent or heavy exposure to known gonadotoxins: radiation, pesticides, excessive heat, solvents and tobacco smoke

❑ Sexual history
* Frequency of intercourse
* Confirm that intravaginal deposition of semen occurs during intercourse (hypospadias)
* Assessment of the female partner’s most fertile window – ideal é ser 48 horas antes da ovulação, uma vez que os espermatozoides sobrevivem cerca de 1 semana dentro do aparelho genital feminino
* Most commercially available sexual lubricants and saliva are spermatotoxic
* Sexual dysfunction

❑ Family history
* Family members with cystic fibrosis, hypospadias or endocrine abnormalities may need more focused genetic evaluation

❑ Female factors
* Age
* Menstrual cycle regularity
* Pregnancy history

Question 15

Diagnostic Evaluation - Physical Examination?

Answer 15

❑ General
* Stature (men with Klinefelter syndrome tend to be tall and ectomorphic with pilous rarefaction)
* Secondary sex characteristics (facial and body hair, gynecomastia, muscle mass)

❑ Phallus
* Hypospadias or other genital disorders (como curvaturas penianas)

❑ Testes
* Size (ideally using an orchidometer), symmetry, position, shape, consistency and presence/ absence of an intratesticular mass
* Reference ranges for testicular dimensions: length of 3.6 to 5.5 cm, a width of 2.1 to 3.2 cm and a volume of about 18 to 20 cc
* Testicles that are soft or small suggest a spermatogenic defect – o tamanho testicular é um bom indicador de fertilidade

Question 16

Diagnostic Evaluation - Physical Examination (2)?

Answer 16

❑ Epididymis
* Dilatation of the epididymal head may suggest obstructive processes within the vas deferens or ejaculatory ducts (elective vasectomy, other obstructive lesions)
* Absence of the epididymis and vas deferens (association with ipsilateral abnormalities of renal development)

❑ Spermatic cord
* Evaluation of the vas deferens along its entire scrotal length
* The vas may be congenitally absent on one or both sides (CBAVD (congenital bilateral absence of the vas deferens) – most common in men with cystic fibrosis or carriers of CFTR gene mutations)
✔ Caso haja ausência bilateral congénita, em 80% dos casos estará associado a mutação dos genes da fibrose cística
* Unilateral absence of the vas may be associated with ipsilateral renal agenesis – implica estudo imagiológico da unidade renal ipsilateral
* Vasectomy – palpable vassal defect

Question 17

Varicocele - Physical Examination?

Answer 17

❑ Varicoceles are present in 15-20% of the general population, but in 35-40% of infertile men – a associação exata entre fertilidade masculina e varicocelo é pouco clara, mas uma meta-análise recente mostrou que varicocelectomia pode melhorar o espermograma, não querendo isto dizer que melhora a fertilidade!
❑ Larger varicoceles (grade 2 and 3) are more often associated with impairment of semen parameters and ipsilateral testicular atrophy with low levels of testosterone – o varicocelo provoca stress oxidativo, provavelmente por aumento da temperatura escrotal, com formação de radicais livres de oxigénio e fragmenta o DNA, piorando a espermatogénese
❑ Unilateral right varicocele should prompt assessment of the right retroperitoneum for lesions obstructing the inferior vena cava with abdominopelvic TAC

Question 18

Rectal examination?

Answer 18

❑ Digital rectal examination
✔ A firm, smooth midline prostatic structure may indicate an obstructing ejaculatory duct cyst, which may be associated with dilatation of the seminal vesicles
✔ Prostate enlargement can be associated with abnormalities of ejaculation

Question 19

Semen Analysis?

Answer 19

❑ The cornerstone of the initial laboratory assessment of the infertile man
❑ Two adequate semen analyses – manter à temperatura corporal e transportar para o laboratório em menos de 1 hora.
❑ Analysis of its physical characteristics (pH and viscosity), volume, sperm concentration, motility, forward progression, morphology, and the presence of round cells.

Question 20

WHO guidelines?

Answer 20

❑ Sperm concentration
– The most critical determinant of fertility potential
– Oligospermia (< 15 *10 6 por mL) (mild (10 a 15), moderate (de 5-10), severe(< 5)), cryptospermia, azoospermia (completa ausência de espermatozoides após centrifugação)

❑ Motility / Capacidade Móvel
– Asthenospermia (baixa percentagem de espermatozoides móveis – motilidade progressiva < 32%)
– Grade 1-4
– Forward progression (grades 3-4)

❑ Morphology (Kruger strict criteria)
– Teratospemia (< 4% de formas normais)

❑ O volume do sémen está diminuído na ejaculação retrógada, na anejaculação e na obstrução dos ductos ejaculatórios.

Question 21

Other semen parameters that may be useful in select cases?

Answer 21

❑ pH
– Useful as an indicator of seminal vesicle patency
– Prostatic secretions are typically acidic, whereas seminal vesicles secretions are basic
– Normal semen has a slightly alkaline pH
– When the semen is acidic, obstruction or absence of the seminal vesicles should be suspected

❑ Fructose
– Useful in the diagnosis of seminal vesicle obstruction or agenesis, as seminal fructose is entirely derived from the seminal vesicles

❑ Viscosity testing is performed 20 to 30 minutes after ejaculation; normal semen has liquefied in this time, while persistently increased viscosity may be related to infection or inflammation

❑ Round cells – may represent leukocytes or immature spermatogonia (leukocyte esterase or peroxidase positivity testing)

❑ Leukocytospermia
– >1 million leukocytes/ml
– Reproductive tract inflammation (oxidative stress) – ocorre na prostatite crónica, por exemplo
– But it is has not been definitively established that leukocytospermia portends a lower chance of conception (via natural or assisted reproductive means)

❑ Post-ejaculatory urine testing to screen for retrograde ejaculation in men with low ejaculate volume (<1.5 ml)

Question 22

Hormone Investigation - The hypothalamic-pituitary-gonadal axis?

Answer 22

❑ Secretion of the anterior pituitary gonadotropin hormones luteinizing hormone (LH) and follicle- stimulating hormone (FSH) are stimulated by the pulsatile release of gonandotropin releasing hormone (GnRH) and inhibited by the release of gonadotropin- inhibiting hormone (GnIH) from the hypothalamus.
❑ Inhibin B is secreted by the testicular germinal epithelium (primarily Sertoli cells) in response to FSH and subsequently acts on the anterior pituitary in a negative-feedback loop, inhibiting FSH production.
❑ Activin has an agonistic effect on the pituitary secretion of FSH and its release is inhibited by inhibin B.

Question 23

Hormone Investigation?

Answer 23

❑ Endocrine testing is recommended in men with oligospermia, azoospermia, or history and physical examination findings suggestive of hormonal abnormalities

❑ Approximately 10% of infertile men will have abnormal serum hormone levels – 2% deles com endocrinopatia

❑ Most endocrinopathies are found in men with sperm concentrations <10 million/mL

❑ Initial hormonal evaluation – FSH and testosterone total
✔ Medir testosterona entre as 8-11 horas da manhã;
✔ A testosterona liga-se muito à SHBG e à albumina, pelo que medir a testosterona biodisponível é mais fiável.

Question 24

Hormone Investigation (2)?

Answer 24

✔ Se testosterona aumentada pode ser devido a testosterona exógena; se diminuída pode ser falência testicular ou diminuição do LH;
✔ A prolactina tem um efeito supressivo sobre as gonadotrofinas, indiretamente afetando a espermatogénese; a prolactina sérica avalia-se quando temos um pan-hipopituitarismo, se a LH e FSH estiverem diminuídas ou se o exame físico for suspeito (com galactorreia, ginecomastia, perda líbido…).

✔ If hyperprolactinemia 🡪 pituitary magnetic resonance imaging (MRI) - para despistar tumor, por exemplo