Premature ovarian failure, categorised under WHO classification group III, is associated with high FSH and low oestrogen levels. Other causes of premature ovarian failure include microdeletions in the X chromosome, surgery and chemotherapy.

Kallmann’s syndrome is a hypogonadotrophic hypogonadism and is associated with low FSH and low oestrogen levels. Other features include anosmia or hyposmia where the sense of smell is completely absent or diminished. Mutations in the KAL1, FGFR1, PROKR2 and PROK2 genes cause Kallmann’s syndrome. Although some of their specific functions are unclear, these genes appear to be involved in the formation and migration of a group of nerve cells that are specialised to process smells (olfactory neurons). These nerve cells come together into a bundle forming the olfactory bulb, which is critical for the perception of odours. The KAL1, FGFR1, PROKR2 and PROK2 genes also play a role in the migration of neurons that produce gonadotrophin-releasing hormone (GnRH).

Carol C, Bolarinde O. The subfertile couple. Obstet Gynaecol Reprod Med. 23:5;154–9.

The strongest independent risk factors for having further miscarriages due to any aetiology are increasing maternal age and number of previous miscarriages. The risk of miscarriage doubles when maternal age doubles from 20 to 40 years. A 1997 longitudinal study found the rate of miscarriage in the next pregnancy to be 25 % in women under 30, 28 % in women aged 31–36 years, 33 % in women aged 36–39 years and 52 % in women over 40 years. Increased paternal age is also associated with miscarriage, with 1.6 times the risk when comparing a paternal age of 40 to that of a 25–29-year-old man. However, recurrent miscarriage has not been linked to any specific paternal health factors.

A poorer prognostic outcome with increasing numbers of miscarriages has been widely documented, with a 53 % chance of further miscarriage with six or more miscarriages versus 29 % with three pregnancy losses. Although, based on these data, 48 % of women over 40 years of age and 47 % of women with more than six previous miscarriages did achieve a live birth in the next pregnancy without having treatment.

Morley L, Shillito J, Tang T. Preventing recurrent miscarriage of unknown aetiology. Obstet Gynaecol. 2013;15:99–105.

Heavy alcohol consumption, but not moderate consumption, may affect sexual and reproductive performance in a reversible fashion. Tobacco smoking and cannabis consumption have been shown to reduce semen parameters, although the relationship between male smoking habits and fertility remains uncertain. Although smokers in general may not experience reduced fertility, men with suboptimal semen quality may benefit from quitting smoking, and this should be strongly encouraged. Varicoceles, a collection of dilated refluxing veins in the spermatic cord, are found in 11.7 % of men with normal semen and 25.4 % of men with abnormal semen. The exact mechanism by which a varicocele can affect fertility is not well understood, but theories include increased scrotal heating and altered testicular steroidogenesis. The diagnostic significance, however, is debatable.

Karavolos S, Stewart J, Evbuomwan I, McEleny K, Aird I. Assessment of the infertile male. Obstet Gynaecol. 2013;15:1–9.

Obstruction, excluding vasectomy, accounts for up to 41 % of causes of azoospermia. The diagnosis is based on normal serum FSH levels, normal testicular volume and evidence of complete spermatogenesis on biopsy. Causes include surgical trauma and vasectomy, infection (chlamydia, gonorrhoea, tuberculosis) and congenital bilateral absence of vas deferens (CBAVD). Treatment options include urological surgery when feasible as in vasectomy reversal or sperm retrieval from testes or epididymides. Techniques for sperm retrieval from the testes include testicular sperm aspiration (TESA), testicular sperm extraction (TESE) and microsurgical TESE (micro-TESE). Sperm from the epididymis can be retrieved by microsurgical (MESA) or percutaneous (PESA) epididymal sperm aspiration under local anaesthetic.

Karavolos S, Stewart J, Evbuomwan I, McEleny K, Aird I. Assessment of the infertile male. Obstet Gynaecol. 2013;15:1–9.

NICE currently recommends the use of up to six cycles of unstimulated IUI in mild cases of male factor infertility in order to reduce the rate of multiple pregnancies. IUI involves the placement of a washed pellet of ejaculated sperm within the uterine cavity, thus bypassing the cervical barrier. It may be performed with or without ovarian stimulation. Other indications include immunologic infertility and mechanical problems of sperm delivery such as erectile dysfunction or hypospadias. NICE recommends that IUI be used in mild forms of oligozoospermia; however, specific semen criteria for its use have not been standardised. Monthly conception rates of 8–16 % have been reported for IUI; however its efficacy has been questioned by recent studies.

National Collaborating Centre for Women’s and Children’s Health. Fertility: assessment and treatment for people with fertility problems. London: RCOG Press; 2004.

Average pregnancy rates of 33.0 % per embryo transfer have been reported after ICSI. Although IVF can be used to treat milder forms of sperm abnormalities, more severe forms require ICSI. ICSI was originally described in 1988 and has since revolutionised the treatment of male factor infertility. It involves the micromanipulation and injection of a single human sperm into the cytoplasm of the oocyte. ICSI requires ovarian stimulation, oocyte retrieval and sperm preparation as for IVF. It is used for uncorrectable severe forms of male factor infertility including oligospermia and asthenoteratozoospermia or following fertilisation failure in a previous IVF cycle.

Karavolos S, Stewart J, Evbuomwan I, McEleny K, Aird I. Assessment of the infertile male. Obstet Gynaecol. 2013;15:1–9.

The most significant short-term complication associated with ovarian stimulation is ovarian hyperstimulation syndrome (OHSS), with moderate or severe OHSS reported in 3–8 % of IVF cycles. The characteristic feature of the pathophysiology of OHSS is increased vascular permeability. This is mediated by vasoactive substances derived from the hyperstimulated ovary following the action of human chorionic gonadotrophin (hCG) or luteinising hormone (LH). Vascular endothelial growth factor (VEGF) appears to play a critical role in the development of OHSS. In vitro studies have shown hCG to be a potent stimulator for granulosa cell VEGF production, which may explain the clinically observed link between hCG exposure and the development of OHSS. Increased vascular permeability is most marked in the peritoneal surfaces nearest to the ovary, leading to ascites, but may also affect pleural and pericardial cavities and the systemic circulation. Loss of fluid into the third space causes hypovolaemia and effusions.

Prakash A, Mathur R. Ovarian hyperstimulation syndrome. Obstet Gynaecol. 2013;15:31–5.

Antiphospholipid antibodies are present in 15 % of women with recurrent miscarriage.

By comparison, the prevalence of antiphospholipid antibodies in women with a low-risk obstetric history is less than 2 %. In women with recurrent miscarriage associated with antiphospholipid antibodies, the live birth rate in pregnancies with no pharmacological intervention has been reported to be as low as 10 %. Adverse pregnancy outcomes associated with APLA include:

http://​www.​rcog.​org.​uk/​files/​rcog-corp/​GTG17recurrentmi​scarriage.​pdf

The main causes of infertility in the UK are:

In about 40 % of cases, disorders are found in both the man and the woman. Uterine or endometrial factors, gamete or embryo defects and pelvic conditions such as endometriosis may also play a role.

NICE. Fertility: assessment and treatment for people with fertility problems. NICE clinical guideline 156. Manchester; 2013. http://​www.​nice.​org.​uk/​nicemedia/​live/​14078/​62769/​62769.​pdf

Polycystic ovarian syndrome is diagnosed when two of the three following criteria are met:

A raised LH:FSH ratio is no longer a diagnostic criteria for PCOS owing to its inconsistency. The diagnosis of PCOS can only be made when other aetiologies have been excluded. The recommended baseline screening tests are thyroid function tests, a serum prolactin and a free androgen index (total testosterone divided by sex hormone-binding globulin (SHBG) × 100 to give a calculated free testosterone level). In cases of clinical evidence of hyperandrogenism and total testosterone greater than 5 nmol/l, 17-hydroxyprogesterone should be sampled and androgen-secreting tumours excluded. If there is a clinical suspicion of Cushing syndrome, this should be investigated according to local practice.

Royal College of Obstetricians and Gynaecologists. Long term consequences of polycystic ovary syndrome. Green-Top guideline No. 33. London: RCOG Press; 2007. http://​www.​rcog.​org.​uk/​files/​rcog-corp/​uploaded-files/​GT33_​LongTermPCOS.​pdf

Women with regular menstrual cycles and more than 1 year’s infertility can be offered a blood test to measure serum progesterone in the midluteal phase of their cycle (day 21 of a 28-day cycle) to confirm ovulation. Progesterone production from the corpus luteum peaks at this time if ovulation has occurred. There is a significant association between smoking and reduced fertility among female smokers. There is inconsistent evidence about the impact of alcohol intake and caffeine on female fertility. Alcohol in excess of 1 unit/day, maternal and paternal smoking and caffeine consumption all have adverse effects on the success rates of assisted reproduction procedures, including IVF. Women who are not known to have comorbidities (such as pelvic inflammatory disease, previous ectopic pregnancy or endometriosis) should be offered hysterosalpingography (HSG) to screen for tubal occlusion because this is a reliable test for ruling out tubal occlusion, and it is less invasive and makes more efficient use of resources than laparoscopy. Women who are thought to have comorbidities should be offered laparoscopy and dye so that tubal and other pelvic pathologies can be assessed at the same time. Women should not be offered an endometrial biopsy to evaluate the luteal phase as part of the investigation of fertility problems because there is no evidence that medical treatment of luteal phase defect improves pregnancy rates.

National Collaborating Centre for Women’s and Children’s Health. Fertility assessment and treatment for people with fertility problems. London: RCOG Press; 2004. http://​www.​rcog.​org.​uk/​files/​rcog-corp/​uploaded-files/​NEBFertilityFull​.​pdf