Foetal Origins of Male Reproductive Disorders

Question 1

What do males have an increased risk of?

Answer 1

• Dying earlier
• Cardiovascular disease
• Kidney disease/hypertension
• Visceral obesity
• Gastric ulcers
• Schizophrenia
• Autistic disorders

Question 2

What disorders in men are associated with lowered testosterone levels?

Answer 2

• Cardiovascular disease
• Hypertension
• Visceral obesity
• Insulin resistance
• Type 2 diabetes
• Steatosis/ dyslipidaemia
• Pro-inflammatory blood profile
• Dying earlier

Question 3

Example of a sentinel marker of cardiovascular disease?

Answer 3

-Erectile dysfunction has similar or greater predictive value for cardiovascular events than traditional risk factors like smoking, hyperlipidaemia and family history of MI (penile arteries narrower than coronary arteries so fur up first)
=especially predictive of CV events in men younger than 60 and in those with diabetes

Question 4

Describe Androgen Insensitivity Syndrome

Answer 4

• Inactivating mutation of AR
• Phenotypically normal female
• Testes (abdominal) are present and are hormonally functional
• Testosterone levels are elevated
• Fallopian tubes, uterus and top part of vagina missing
• Body fat distribution is female
• Brain is female

Question 5

What behaviours and skills are different in females or males?

Answer 5

• Males= more risk-taking behaviours, associated with sexual urge
• Females have poorer visual-spacial skills

Question 6

What is the prevalence of new-born male reproductive disorders?

Answer 6

• Cryptorchidism 6-9%

- Hypospadias 0.4-0.9%

Question 7

What is the prevalence of young adult male reproductive disorders?

Answer 7

• Low sperm count 16-20%
• Testis germ cell cancer 0.45%
• Low adult testosterone (compensated Leydig cell failure) 10%

Question 8

Describe Testicular dysgenesis syndrome

Answer 8

-Testosterone action deficiency in foetal life increases likelihood?
=Cryptorchidism and hypospadias
=Testis GC cancer, low sperm count and low-normal T levels
=may reduce penis size

Question 9

What is Cryptorchidism?

Answer 9

-Failure of one or more testes to descend to the scrotum before birth
=one of the commonest congenital malformations in children (2-4% boys at birth)

Question 10

What is Hypospadias?

Answer 10

-Opening of penis is underside rather than tip

=further down increases severity

Question 11

What causes Cryptorchidism?

Answer 11

-Final, androgen-dependent phase into scrotum

Question 12

Describe testicular germ cell cancer

Answer 12

-Risk decreases as you get older
=peak incidence 25-30
=rare cancer
lifetime risk 0.45%
=incidence has been increasing, environmental lifestyle?

Question 13

How does testicular germ cell cancer occur?

Answer 13

-Origins in foetal life
-‘Faulty’ Sertoli cells suspected cause (support germ cells, pluripotent cells)
=determine sperm count

Question 14

Why is falling sperm count a problem?

Answer 14

-Lower proportion of couple fertility at first try for a baby
=lower sperm count decrease chances of pregnancy decrease
=matters more as societal changes mean women have babies older so chances already decreased
=increased time to achieve pregnancy and increased use of assisted reproduction (ICSI= intracytoplasmic sperm injection)

Question 15

What are the problems with assisted reproduction?

Answer 15

• Assisted reproduction is at best ~30% successful
• It gets increasingly ineffective with age
• It is a bruising, traumatic process (especially for the female partner)
• It can be expensive and there may be a significant waiting list
• The main invasive treatment for ICSI is to female partner

Question 16

What are the big health unknowns for IVF and ISCI?

Answer 16

-Variation in nutrition around the time of conception (before implantation) can dramatically alter metabolic function of the offspring in adulthood
=These effects may be passed on to the next generation (grandchildren)
-In IVF, embryos are cultured for several days
-Sperm can also pass on epigenetic effects to offspring/grand-offspring which can alter their metabolism and health
-Long-term effects of ICSI on health of offspring are largely unknown; sperm counts are 50% lower in ICSI-derived human males

Question 17

How does Sertoli cell number affect sperm count?

Answer 17

-Number of Sertoli cells determines how many germ cells are supported so how many sperm you can make
=Each Sertoli cell can support a fixed number of germ cells during their 10-week development into sperm
=varies >100 fold between men (as does sperm count), mainly determined during foetal/ early postnatal life

Question 18

What is Anogenital distance (AGD)?

Answer 18

-Distance between centre of anal opening and base of scrotum or penis in males
=Twice as long in males than females
=determined by foetal androgen exposure in narrow window (masculinization programming window)
=decreased increases abnormalities and AGD

Question 19

When is the MPW?

Answer 19

-Masculinization programming window in humans within period 8-12 weeks

Question 20

What maternal lifestyle factors influence sperm count?

Answer 20

• Smoking (up to 40% reduction)
• > 90% of research effort in this area over the last 20 years has focussed on exposure to environmental contaminants/pollutants (‘endocrine disruptors’)
• The biggest changes have been to maternal diet and lifestyle
• Use of medicines during pregnancy has also increased substantially (acetaminophen/ painkiller)

Question 21

Describe germ cells

Answer 21

• Future fertility absolutely dependent on germ cells from both sexes
• First cells to differentiate in embryo and foetal germ cells are the source of adult fertility (and potentially health of resulting offspring)

Question 22

What are the results of analgesic exposure in pregnancy?

Answer 22

• Reduced GC number in male and female offspring resulting in reduced female adult fertility
• Impaired ovarian function in grand-daughters
• The grand-daughter effects were transmitted via exposed fathers as well as mothers