Infertility
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Infertility\: failure to conceive after one year or more of frequent, unprotected sexual intercourse; a
the UK.
80% conceive within 1 year, 90% within 2 years.
Classi
Primary\: couples who have never conceived.
Secondary\: couples who have previously conceived.
Main causes in the UK\:
Male factor infertility (30%).
Ovulatory causes (25%).
Tubal causes (20%).
Uterine/peritoneal causes (10%).
In 40% of a
Female factor infertility\:
Ovulatory disorders\:
Group I\: hypothalamic-pituitary failure (e.g., hypogonadotropic hypogonadism).
Group II\: hypothalamic-pituitary-ovulation dysfunction (e.g., PCOS).
Group III\: ovarian failure (e.g., hypergonadotropic hypogonadism).
Other causes\: Sheehan’s syndrome, hyperprolactinaemia, pituitary tumours.
Tubal causes\: pelvic in
Uterine/peritoneal causes\: endometriosis, cervical mucus dysfunction, previous surgery, uterine
syndrome, previous abdominal infections, congenital abnormalities.
Male factor infertility\:
Semen abnormalities\:
Oligospermia\: \< 15 million sperm/ml.
Teratospermia\: \< 4% normal morphology.
Asthenospermia\: \< 32% motility.
Azoospermia\: no sperm in ejaculate.
Types\:
Obstructive infertility\: e.g., previous vasectomy, cystic
Non-obstructive infertility\: e.g., hormonal causes, varicocele, genetic causes, cryptorchidism, testicular trauma or
malignancy.
Coital infertility\: e.g., erectile dysfunction, premature ejaculation, anejaculation, retrograde ejaculation, penile deformities.
Initial investigations (primary care)\:
Male\: semen analysis, chlamydia screen.
Female\: mid-luteal progesterone, FSH and LH, chlamydia screen.
Further investigations (secondary care)\:
Male\: hormone analysis, genetic testing, ultrasound, testicular biopsy, viral screen (HIV, Hepatitis B and C).
Female\: tubal patency tests (HSG, laparoscopy and dye), ovarian reserve tests (antral follicle count, AMH, FSH), viral screen.
Preconception lifestyle advice\:Regular intercourse (every 2-3 days).
400 micrograms folic acid daily (5mg if high risk for neural tube defects).
Smoking cessation.
Reduce excessive alcohol intake.
Optimise weight; obesity a
Healthy diet and regular exercise.
Loose-
Female factor infertility management\:
Medical\: clomiphene, gonadotrophins, pulsatile GnRH, dopamine agonists.
Surgical\: tubal surgery for mild tubal disease.
Male factor infertility management\:
Medical\: gonadotrophins for hypogonadotropic hypogonadism.
Surgical\: correction of genital tract blockages.
Assisted conception\:
IUI\: partner or donor sperm, inseminated during natural or stimulated cycles.
IVF\: for severe tubal disease, unexplained infertility, or failed other treatments.
ICSI\: injecting sperm directly into an oocyte; for low sperm count or sexual dysfunction.
Donor insemination\: for persistent azoospermia, no sperm on testicular biopsy.
Oocyte donation\: for ovarian failure or absent ovaries.
Embryo donation.
Complications of assisted conception\: OHSS, multiple pregnancy, ectopic pregnancy, pelvic infection.
Psychological support\: counselling recommended before, during, and after investigations and treatment.
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A comprehensive topic overview
Introduction
Infertility is de
” It is
estimated that 1 in 7 couples are a
1
80% of couples trying to conceive will do so within 1 year. Half of the couples who did not conceive in the
conceive in the second, resulting in an overall pregnancy rate in 2 years of 90%.
1
Infertility can be classed as\:
Primary - couples who have never conceived
Secondary - couples who have previously conceived
Hypothalamic-pituitary-gonadal (HPG) axis
To fully understand the topic of infertility and actions of infertility drugs, it is useful to have an overview of the
hypothalamic-pituitary-gonadal (HPG) axis (Figure 1).
The hypothalamus releases gonadotrophin-releasing hormone (GnRH). GnRH acts on the anterior pituitary to stimulate the
secretion of follicle-stimulating hormone (FSH) and luteinising hormone (LH).
In females, LH and FSH then stimulate the ovaries to produce progesterone and oestrogen. When there are moderate
levels of oestrogen, or oestrogen is secreted in the presence of progesterone, negative feedback on the HPG axis inhibits
GnRH release.
However, when there are high levels of oestrogen present, positive feedback on the HPG axis stimulates the hypothalamus
to secrete GnRH.In males, LH acts on Leydig cells within the testes to produce testosterone. Testosterone and FSH then interact with Sertoli
cells to stimulate sperm development. Testosterone also provides negative feedback to the hypothalamus to suppress
GnRH secretion.
Figure 1. Female and male HPG axis
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Causes of infertility
The main causes of infertility in the UK are\:
Male factor infertility (30%)
Ovulatory causes for infertility (25%)
Tubal causes for infertility (20%)
Uterine/peritoneal causes for infertility (10%)
In 40% of a
1
Female factor infertility
Causes of female factor infertility are commonly separated into\:
Disorders of ovulation
Tubal causes
Uterine/peritoneal causes
Disorders of ovulation
To understand pathological processes that can a
(read our guide here). There are 3 main types of ovulatory disorders.
Group I - hypothalamic-pituitary failure
Hypogonadotropic hypogonadism\: There is a failure to produce the required amount of LH and FSH, resulting in
anovulation.
Group II - hypothalamic-pituitary-ovulation dysfunction
This occurs as the result of polycystic ovary syndrome (PCOS) - the most common cause of female infertility.
Group III -ovarian failure
Hypergonadotropic hypogonadism\: There is normal hypothalamic and pituitary function but there are insu
numbers of follicles within the ovary. Therefore, there is less oestrogen produced and follicles do not develop fully. Thisresults in anovulatory cycles.
2
Other ovulatory causes include\:
Sheehan’s syndrome - Hypopituitarism caused by ischaemic necrosis of the pituitary. This occurs as the result of severe
hypotension or haemorrhagic shock secondary to massive post-partum haemorrhage.
Hyperprolactinaemia - This inhibits both FSH and LH secretion and can lead to menstrual dysfunction and
galactorrhoea.
Pituitary tumours - The tumour displaces or destroys normal pituitary tissue and can a
LH.
2
Tubal causes
The delicate structure of the fallopian tubes makes them more susceptible to damage. The most common cause of tubal
damage is due to pelvic in
Other tubal causes include\:
Previous sterilisation
Endometriosis
Previous pelvic surgery
Uterine/peritoneal causes
The most prevalent uterine or peritoneal cause is endometriosis, which causes in
that can distort pelvic anatomy.
Other uterine/peritoneal causes include\:
Cervical mucus dysfunction or defect
Previous pelvic or cervical surgery
Uterine
Asherman’s syndrome
Previous abdominal infections which have resulted in adhesions (e.g. appendicitis)
Congenital abnormalities
Male factor infertility
Traditionally, male factor infertility is diagnosed by observing sperm abnormalities during semen analysis. Semen analysis
assesses sperm count, motility, morphology, vitality, concentration and volume.
Potential abnormalities on semen analysis include\:
Oligospermia - \< 15 million sperm per ml
Teratospermia - \< 4% normal morphology
Asthenospermia - \< 32% sperm motility
Azoospermia - no sperm found within the ejaculate
1,3
Male factor infertility can be classi
Obstructive infertility - a problem with the sperm delivery
Non-obstructive infertility - a problem with the sperm production
Coital infertility - infertility secondary to sexual dysfunction
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Obstructive infertility
Previous vasectomy - the most common cause of obstructive azoospermia
Cystic
Ejaculatory duct obstruction - can be caused by previous prostatitis, leading to
congenital prostatic cysts
Epididymal obstruction - may occur secondary to a chlamydia or gonorrhoea infection which can cause in
and
Non-obstructive infertility
Hormonal causes- hypogonadotropic hypogonadism, hyperprolactinaemia - causes infertility secondary to impotence
Varicocele - is associated with impaired testicular function and infertility
Genetic causes\:Klinefelter’s syndrome (47, XXY) - This is the most common genetic disorder associated with infertility. It is associated
with hypogonadism and defects of spermatogenesis.
Androgen insensitivity syndrome - Child with XY karyotype appearing female due to resistance of the virilising actions
of androgens. When there is limited resistance to androgens, there may be poor development of the testes.
Kallmann syndrome - This is a form of hypogonadotropic hypogonadism. Males a
usually have undescended testes and a micropenis. The lack of sex hormone production often causes a lack of
development of secondary sexual characteristics.
3
Cryptorchidism (undescended testes)
Previous testicular trauma or damage (e.g. testicular torsion)
Testicular malignancy
Coital infertility
Erectile dysfunction - when severe, there may be di
Premature ejaculation - when severe, ejaculation may occur before vaginal penetration
Anejaculation\:
Primary - may occur due to psychosexual or neurological causes
Secondary - may occur due to previous abdominal/pelvic surgery or certain drugs such as antidepressants or alpha-
blockers
Retrograde ejaculation
Penile deformities (e.g. Peyronie’s disease, hypospadias)
Investigations
Investigations for infertility may be commenced in couples who have been trying to conceive for 1 year after frequent
(every 2-3 days), unprotected sexual intercourse.
Couples can have an early referral for infertility investigations, after 6 months of unsuccessful attempts to conceive, if they
meet the following criteria\:
The woman is aged 36 years or older or
There is a known cause of infertility or
There is a history of predisposing factors
*Immediate assessment and treatment of couples may be warranted when the woman is aged 40 years or older.
1
Initial investigations
These investigations may be requested in primary care.
Male
Semen analysis - this assesses the sperm count, motility, morphology, vitality, concentration and volume.
Chlamydia screen
3
Female
Mid-luteal progesterone (day 21 or equivalent in the woman’s cycle) - to assess whether the woman is ovulating
FSH and LH to assess ovarian function - poor ovarian function may be indicated by high levels of both FSH and LH
Chlamydia screen
2
Further investigations
These are often conducted in secondary care.
Male
Hormone analysis - testosterone, FSH, LH and prolactin
Genetic testing
Ultrasound - to investigate any potential structural abnormality
Testicular biopsy - to both de
Viral screen - HIV, Hepatitis B and Hepatitis C screening should be o
3
FemaleInvestigations for tubal patency\:
Hysterosalpingogram (HSG)
Laparoscopy and dye - usually o
Investigations of the ovarian reserve\:
One of the following should be measured on day 3 of the woman’s cycle to predict the ovarian response to
gonadotrophin stimulation in IVF treatment\:
Total antral follicle count
Anti-Mullerian hormone (AMH) (low count= premature ovarian failure)
FSH
Viral screen - HIV, Hepatitis B and Hepatitis C screening should be o
2
Management
Initial preconception lifestyle advice, which ideally would be given in primary care\:
Encourage regular intercourse - every 2-3 days
400 micrograms folic acid daily(take 5mg daily if high risk for neural tube defects e.g. diabetes, on anti-epileptics etc.)
Smoking cessation
Reduce alcohol intake if excessive - as known to impair fertility
Optimise weight - obesity in women is associated with PCOS, miscarriage, lower success with assisted reproductive
technologies and increased risk of obstetric complications. Being overweight can also impair fertility in males.
Healthy diet and regular exercise
Men to wear loose-
Female factor infertility
Medical management
Medication to stimulate ovulation. Consult your local BNF for appropriate dosages.
Clomiphene - an anti-oestrogen drug\:
5
Clomiphene induces ovulation by inhibiting oestrogen from binding in the anterior pituitary. This stops the negative
feedback mechanism of oestrogen, thus the secretion of GnRH, FSH and LH increases. This results in greater
stimulation of the ovaries and therefore a greater increase in oestrogen production and secretion. The oestrogen
stimulates follicle growth and maturation.
6
Gonadotrophins - can be given when there is clomiphene-resistant anovulatory infertility
Pulsatile GnRH\:
GnRH must be given in a pulsatile fashion to stimulate the release of gonadotrophins.
GnRH given continuously actually has an inhibitory e
Dopamine agonists - these can be bene
5
Surgical management
Tubal surgery\:
Used for women with mild tubal disease.
This includes tubal catheterisation or tubal cannulation to improve the chance of a spontaneous pregnancy.
1,5
Male factor infertility
Medical management
Gonadotrophins may be given in men with hypogonadotropic hypogonadism
5
Surgical management
fertility.
1,5
Surgical correction of any blockage within the male genital tract should be o
Assisted conception methods for female and male factor infertilityAssisted conception refers to procedures which cause sperm to come into proximity with oocytes to promote conception. It
includes\:Intrauterine insemination (IUI) - this uses partner or donor sperm and is inseminated during natural or stimulated cycles
In vitro fertilisation (IVF) - this method is bene
unexplained infertility or they have found other treatments to be unsuccessful
Intracytoplasmic sperm injection (ICSI) - this procedure involves injecting a sperm directly into an oocyte. This is a
suitable option for men with a low sperm count or with sexual dysfunction.
Donor insemination - this may be used when the man su
sperm identi
Oocyte donation - this is a suitable option when the woman has ovarian failure or there is an absence of the ovaries
Embryo donation
1,5
Complications of assisted conception
These can include\:
Ovarian hyperstimulation syndrome (OHSS) - this is a potentially life-threatening complication of superovulation
Multiple pregnancy
Ectopic pregnancy
Pelvic infection
1
Psychological support for couples with infertility
The diagnosis of infertility is associated with signi
help couples a
consider a couple’s mental health throughout this process.
NICE recommends o
counselling should be o
procedures.
1
References
NICE Guideline CG156. F e r t i l i t y p r o b l e m s \: a s s e s s m e n t a n d t r e a t m e n t . Published in 2013. [LINK]
Smith S, Pfeifer S, Collins J. Diagnosis and Management of Female Infertility. JAMA. 2003;290(13)\:1767.
Karavolos S, Stewart J, Evbuomwan I, McEleny K, Aird I. Assessment of the infertile male. The Obstetrician & Gynaecologist.
2013;15(1)\:1-9.
Abdel Raheem A, Ralph D, Minhas S. Male infertility. British Journal of Medical and Surgical Urology. 2012;5(5)\:254-268.
Nandi A, Homburg R. Unexplained subfertility\: diagnosis and management. The Obstetrician & Gynaecologist.
2016;18(2)\:107-115.
Rang, H.P. & Dale, M. Maureen.Rang & Dale's Pharmacology. 7th ed. Edinburgh\: Elsevier Churchill Livingstone; 2012. [LINK]
Lu Kong, Ting Zhang, Meng Tang and Dayong Wang. F e m a l e H C G a x i s . [CC BY] [LINK]
Lu Kong, Ting Zhang, Meng Tang and Dayong Wang. M a l e H C G a x i s . [CC BY] [LINK]
Reviewer
Dr Brenda Narice
Obstetrics & Gynaecology Registrar
Editor
Hannah Thomas
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Contents
Introduction
Hypothalamic-pituitary-gonadal (HPG) axis
Causes of infertility
Investigations
Management
Source\: geekymedics.com