Chapter 14 – Causes and Investigation of Ovarian Infertility




Abstract




Conventional ovulation induction (OI) treatments are highly effective in achieving pregnancy when anovulation is the only factor in a couple’s conception delay. Fertility declines with female age and lifestyle factors including smoking, alcohol intake and body weight negatively influence the success of treatment. Careful planning and monitoring of treatment is necessary to avoid complications such as multiple pregnancy and ovarian hyperstimulation syndrome (OHSS).





Chapter 14 Causes and Investigation of Ovarian Infertility



Adam H. Balen



1 Introduction


Conventional ovulation induction (OI) treatments are highly effective in achieving pregnancy when anovulation is the only factor in a couple’s conception delay. Fertility declines with female age and lifestyle factors including smoking, alcohol intake and body weight negatively influence the success of treatment. Careful planning and monitoring of treatment is necessary to avoid complications such as multiple pregnancy and ovarian hyperstimulation syndrome (OHSS).



2 Aetiology


Ovulatory disorders are broadly classified by World Health Organization (WHO) as follows:




  • Group I: hypothalamic pituitary failure (hypothalamic amenorrhoea or hypogonadotrophic hypogonadism)



  • Group II: hypothalamic pituitary dysfunction (normogonadotrophic, predominately polycystic ovary syndrome).



  • Group III: ovarian failure (hypergonadotrophic anovulation)


Table 14.1




Table 14.1 Gonadotrophin and oestradiol profiles in different clinical scenarios




























Ovarian failure ↑ FSH ↑ LH ↓ Oestradiol
Hypothalamic or pituitary failure ↓ FSH ↓ ↓ LH ↓ Oestradiol
PCOS n/↓ FSH n/↑ LH n/↑ Oestradiol
Mid-cycle, preovulatory ↑ FSH ↑↑ LH ↑ Oestradiol


3 History and Examination


Menstrual cycles are considered regular if they fall in the range of 23 to 35 days and have a month-to-month variation in cycle length of less than five days. It is estimated that at least 90–95% of normally menstruating women have ovulatory cycles. Women suspected of ovulatory dysfunction need careful assessment with appropriate investigations in order to be able to tailor treatment accordingly.


Measurement of height and weight should be performed in order to calculate the patient’s body mass index (BMI). The normal range is 20–25 kg/m2, and a value above or below this may suggest a diagnosis of weight-related amenorrhoea (which is a term usually applied to underweight women).


Signs of hyperandrogenism (acne, hirsutism, balding [alopecia]]) are suggestive of polcystic ovary syndrome (PCOS), although biochemical screening helps to differentiate other causes of androgen excess. It is important to distinguish between hyperandrogenism and virilization, which also occurs with high circulating androgen levels and causes deepening of the voice, breast atrophy, increase in muscle bulk and cliteromegaly. A rapid onset of hirsutism suggests the possibility of an androgen-secreting tumour of the ovary or adrenal gland. Hirsutism can be graded and given a ‘Ferriman Gallwey Score’ by assessing the amount of hair in different parts of the body (e.g. upper lip, chin, breasts, abdomen, arms, legs). It is useful to monitor the progress of hirsutism, or its response to treatment, by making serial records, either by using a chart or by taking photographs of affected areas of the body. It should be remembered, however, that not all hair on the body is necessarily responsive to hormone changes (for example the upper thighs). There may also be big ethnic variations in the expression of hirsutism, with women from South Asia and Mediterranean countries often having more pronounced problems, whereas those from the Far East may not have much in the way of bodily hair. Furthermore the degree of hirsutism does not correlate that well with the actual levels of circulating androgens.


A measurement of total testosterone (T) is considered adequate for general screening (Box 14.1). It is unnecessary to measure other androgens unless total T is > 5 nmol/L (this will depend on the normal range of your local assay). Insulin may be elevated in overweight women and suppresses the production of sex hormone–binding globulin (SHBG) by the liver, resulting in a high free androgen index (FAI) in the presence of a normal total T. The measurement of SHBG is not required in routine practice but is a useful surrogate marker for insulin resistance (IR).




Box 14.1 Endocrine normal ranges



Follicle-stimulating hormone, FSH

1–10 IU/L (early follicular)


Luteinizing hormone, LH

1–10 IU/L (early follicular)


Prolactin

< 400 mIU/L


Thyroid-stimulating hormone, TSH

0.5–4.0 IU/L


Thyroxine (T4)

50–150 nmol/L


Free T4

9–22 pmol/L


Tri-iodothyronine (T3)

1.5–3.5 nmol/L


Free T3

4.3–8.6 pmol/L


Thyroid-binding globulin, TBG

7–17 mg/L


Testosterone (T)

0.5–3.5 nmol/L (ranges depend upon the assay being used)


Sex hormone-binding globulin, SHBG

16–120 nmol/L


Free androgen index [(T × 100) ÷ SHBG]

< 5


Dihydrotestosterone

0.3–1 nmol/L


Androstenedione

2–10 nmol/L


Dehydroepiandrosterone sulphate

3–10 μmol/L


Cortisol
8 a.m.

140–700 nmol/L


Midnight

0–140 nmol/L


24-hour urinary

< 400 nmol/24 h


Oestradiol

250–500 pmol/L


Progesterone (mid-luteal)

> 25 nmol/L to indicate ovulation


17-hydroxyprogesterone

1–20 nmol/L


Anti-Mullerian hormone (AMH)

Values should be assessed with respect to age-related nomograms. Low levels indicate poor ovarian reserve, normal levels suggest normal fertility and high values are often seen in women with polycystic ovaries.


One should be aware of the possibility of Cushing’s syndrome in women with stigmata of PCOS and obesity as it is a disease of insidious onset and dire consequences; additional clues are the presence of central obesity, moon face, plethoric complexion, buffalo hump, proximal myopathy, thin skin, bruising and abdominal striae (which alone are a common finding in obese individuals). Acanthosis nigricans (AN) is a sign of profound insulin resistance and is usually visible as hyperpigmented thickening of the skin folds of the axilla and neck; AN is associated with PCOS and obesity.


A testosterone concentration > 5 nmol/L should be investigated to exclude androgen-secreting tumours of the ovary or adrenal gland, Cushing’s syndrome and late-onset congenital adrenal hyperplasia (CAH). Whereas CAH often presents at birth with ambiguous genitalia, partial 21-hydroxylase deficiency may present in later life, usually in the teenage years, with signs and symptoms similar to PCOS. In such cases, T may be elevated and the diagnosis confirmed by an elevated serum concentration of 17-hydroxyprogesterone (17-OHP); an abnormal ACTH-stimulation test may also be helpful (250 µg ACTH will cause an elevation of 17-OHP, usually between 65–470 nmol/L).


In cases of Cushing’s syndrome, a 24-hour urinary-free cortisol will be elevated (> 700 nmol/24 hours). The normal serum concentration of cortisol is 140–700 nmol/L at 8 a.m. and less than 140 nmol/L at midnight. A low-dose dexamethasone suppression test (0.5 mg six-hourly for 48 hours) will cause a suppression of serum cortisol by 48 hours. A simpler screening test is an overnight suppression test, using a single midnight dose of dexamethasone 1 mg (2 mg if obese) and measuring the serum cortisol concentration at 8 a.m. when it should be less than 140 nmol/L. If Cushing’s syndrome is confirmed, a high-dose dexamethasone suppression test (2 mg six-hourly for 48 hours) should suppress serum cortisol by 48 hours if there is a pituitary ACTH-secreting adenoma (Cushing’s disease); failure of suppression suggests an adrenal tumour or ectopic secretion of ACTH; further tests and detailed imaging will then be required.


The measurement of other serum androgen levels can be helpful. Dehydroepiandrosterone sulphate (DHEAS) is primarily a product of the adrenal androgen pathway (normal range < 10 μmol/l). If the serum androgen concentrations are elevated, the possibility of an ovarian or adrenal tumour should be excluded by ultrasound or CT scans. The measurement of androstenedione can also be useful in some situations.


Amenorrhoiec women might have hyperprolactinaemia and galactorrhoea. It is important, however, not to examine the breasts before taking blood as the serum prolactin concentration may be falsely elevated as a result of physical examination. Stress may also cause minor elevation of prolactin. If there is suspicion of a pituitary tumour, the patient’s visual fields should be checked, as bitemporal hemianopia secondary to pressure on the optic chiasm requires urgent attention.


Thyroid disease is common and the thyroid gland should be palpated and signs of hypothyroidism (dry thin hair, proximal myopathy, myotonia, slow-relaxing reflexes, mental slowness, bradycardia, etc.) or hyperthyroidism (goitre with bruit, tremor, weight loss, tachycardia, hyper-reflexia, exopthalmos, conjunctival oedema, ophthalmoplegia) elicited.


A baseline assessment of the endocrine status should include the measurement of serum prolactin and gonadotrophin concentrations and an assessment of thyroid function. Prolactin levels may be elevated in response to a number of conditions, including stress, a recent breast examination or even having a blood test. The elevation, however, is moderate and transient. A more permanent, but still moderate, elevation (greater than 700 mIU/L) is associated with hypothyroidism and is also a common finding in women with PCOS, where prolactin levels up to 2500 mIU/L have been reported. PCOS may also result in amenorrhoea, which can therefore create diagnostic and hence appropriate management difficulties, for those women with hyperprolactinaemia and polycystic ovaries. Amenorrhoea in women with PCOS is secondary to acyclical ovarian activity, yet oestrogen production by the ovaries continues and so the endometrium will be greater than 6 mm. A positive response to a progestogen challenge test (e.g. medroxyprogesterone acetate 10–20 mg [depending on body weight] daily for seven days), which induces a withdrawal bleed, will distinguish patients with PCOS-related hyperprolactinaemia from those with polycystic ovaries and unrelated hyperprolactinaemia, because the latter causes oestrogen deficiency and therefore failure to respond to the progestogen challenge because the endometrium is thin.


A serum prolactin concentration of greater than 1000 mIU/L warrants a repeat and then further investigation if still elevated. Computed tomography (CT) or magnetic resonance imaging (MRI) of the pituitary fossa may be used to exclude a hypothalamic tumour, a non-functioning pituitary tumour compressing the hypothalamus or a prolactinoma. Serum prolactin concentrations greater than 5000 mIU/L are usually associated with a macroprolactinoma, which by definition is greater than 1 cm in diameter.


Serum measurements of oestradiol are of limited value as they vary considerably, even in a patient with amenorrhoea. If the patient is well oestrogenized, the endometrium will be clearly seen on an ultrasound scan and should be shed on withdrawal of the progestogen.


Serum gonadotrophin measurements help to distinguish between cases of hypothalamic or pituitary failure and gonadal failure. Elevated gonadotrophin concentrations indicate a failure of negative feedback as a result of primary or premature ovarian insuffiency (POI, formerly known as premature ovarian failure). A serum follicle-stimulating hormone (FSH) concentration of greater than 15 IU/L that is not associated with a preovulatory luteinizing hormone (LH) surge suggests impending ovarian failure. FSH levels of greater than 40 IU/L are suggestive of irreversible ovarian failure. The exact values vary according to individual assays, and so local reference levels should be checked. It is also important to assess serum gonadotrophin levels at baseline, that is, during the first three days of a menstrual period. In patients with oligo/amenorrhoea, it may be necessary to perform two or more random measurements, although combining an assessment of endocrinology with an ultrasound scan on the same day aids the diagnosis.


An elevated LH concentration, when associated with a raised FSH concentration, is indicative of ovarian failure. However, if LH is elevated alone (and is not attributable to the preovulatory LH surge), this suggests PCOS. This may be confirmed by a pelvic ultrasound scan. Rarely, an elevated LH in a phenotypic female may be due to androgen insensitivity syndrome (AIS), although this condition presents with primary amenorrhoea.


Inhibin B is thought to be the ovarian hormone which has the greatest influence on pituitary secretion of FSH. Previously, it was thought that serum concentrations of inhibin B might provide better quantification of ovarian reserve than serum FSH concentrations, however, the assay is no longer being used.


Anti-Mullerian hormone (AMH) is best known as a product of the testes during fetal development that suppresses the development of Mullerian structures. AMH is also produced by the preantral and antral follicles and appears to be a more stable predictor of the ovarian follicle pool as it does not fluctuate through the menstrual cycle. Indeed, it has been reported that higher AMH concentrations are associated with increased numbers of mature oocytes, embryos and clinical pregnancies during in vitro fertilization (IVF) treatment. Assays for AMH are now available for routine use and it is this hormone that currently offers the greatest promise for future assessment of ovarian reserve and function. The number of antral follicles in the ovary, as assessed by pelvic ultrasound, also correlates well with ovarian reserve and serum AMH levels. Indeed, it is the number of small antral follicles, 2–6 mm in diameter, that declines significantly with age while there is little change in the larger follicles of 7–10 mm, which is still below the size at which growing follicles have been recruited.


Failure at the level of the hypothalamus or pituitary is reflected by abnormally low levels of serum gonadotrophin concentrations, and gives rise to hypogonadotrophic hypogonadism. Kallmann’s syndrome is the clinical finding of anosmia and/or colour blindness associated with hypogonadotrophic hypogonadism – usually a cause of primary amenorrhoea. CT or MRI should be performed if indicated.


Women with premature ovarian insufficiency (POI) (under the age of 40 years) may have a chromosomal abnormality (e.g. Turner syndrome [45X or 46XX/45X mosaic] or other sex chromosome mosaicisms). A number of genes have also been associated with familial POF, but have not been assessed in routine clinical practice. An autoantibody screen should also be undertaken in women with POI, although it can be difficult to detect antiovarian antibodies and many will have evidence of other autoantibodies (e.g. thyroid), which then indicates the need for further surveillance.


Measurement of bone mineral density (BMD) is indicated in amenorrhoeic women who are oestrogen-deficient. Measurements of density are made in the lumbar spine and femoral neck. The vertebral bone is more sensitive to oestrogen deficiency and vertebral fractures tend to occur in a younger age group (50–60 years) than fractures at the femoral neck (70+ years). However, it should be noted that crush fractures can spuriously increase the measured BMD. An X-ray of the dorsolumbar spine is therefore often complimentary, particularly in patients who have lost height.


Amenorrhoea may also have long-term metabolic and physical consequences. In women with PCOS and prolonged amenorrhoea, there is a risk of endometrial hyperplasia and adenocarcinoma. If on resumption of menstruation there is a history of persistent intermenstrual bleeding, or on ultrasound there is a postmenstrual endometrial thickness of greater than 10 mm, an endometrial biopsy is indicated.


Serum cholesterol measurements are important because of the association of an increased risk of heart disease in women with POI. Women with PCOS, although not oestrogen-deficient, may have a subnormal high-density lipoprotein (HDL): total cholesterol ratio. This is as a consequence of the hypersecretion of insulin that occurs in many women with PCOS.



3.1 Glucose Tolerance


Women who are obese, and also many slim women with PCOS, may have insulin resistance and elevated serum concentrations of insulin (usually < 30 mIU/L fasting, although not measured in clinical practice). A 75 g oral glucose tolerance test (GTT) should be performed in women with PCOS and a BMI > 30 kg/m2, with an assessment of the fasting and two-hour glucose concentration (Table 14.2). It has been suggested that South Asian women should have an assessment of glucose tolerance if their BMI is greater than 25 kg/m2 because of the greater risk of insulin resistance at a lower BMI than seen in the white Caucasian population.


Oct 26, 2020 | Posted by in GYNECOLOGY | Comments Off on Chapter 14 – Causes and Investigation of Ovarian Infertility
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