Amenorrhoea

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Chapter 2 Amenorrhoea

Michael Flynn

Puberty

Definition. Puberty is the physiological developmental stage of becoming capable of reproduction (ovulation in the female and spermatogenesis in the male).

Endocrinology of puberty

In the fetus, the hypothalamic–pituitary axis responsible for pubertal development is able to function normally, but chronic inhibitory tone secondary to high levels of sex hormones from the fetoplacental unit inhibits fetal gonadotrophin release. After birth, increasing central nervous inhibition prevents gonadotrophin secretion. Puberty occurs when the gradual rise in gonadotrophin-releasing hormone (GnRH) secretion stimulates the pituitary to release gonadotrophin. With the lowering in central nervous system inhibition, there is an increase in hypothalamic generation of GnRH and increasing ovarian sensitivity to gonadotrophins.

Secondary sexual characteristics

Major physical changes during puberty

• development of secondary sexual characteristics

• changes in body mass and fat distribution

• rapid skeletal growth, with fusion of epiphyses

Secondary female characteristics

These include the enlargement of the ovaries, uterus, vagina, labia and breasts, and the growth of pubic hair.

• Breast development (thelarche) is classified into Tanner stages 1–5. Development normally starts between 8 and 13 years of age. It is the first physical sign of puberty and is primarily controlled by ovarian oestrogens.

• Pubic hair growth usually begins with the appearance of breast buds. It is under the control of adrenal androgens. There is a high correlation between breast and pubic hair stages.

• Growth in height usually occurs, with the peak growth velocity coinciding with Tanner stages 2–3 (at about 12 years of age). In the year of maximum growth, 6–11 cm is added to the height.

• Axillary hair growth begins at about 12.5–13 years of age. It takes about 15 months from the first appearance of axillary hair to achieve adult distribution.

• Menarche occurs at the average age of 13 years (range 12.2–14.2 years). It occurs within 2 years of the onset of breast development, regardless of the age at which this occurs. Menarche occurs after the peak of the growth spurt in height.

• Skeletal age corresponds better to maturity than chronological age.

• Vaginal length increases before the development of secondary sexual characteristics. There is also enlargement of the vulva.

• Uterine growth is mainly due to enlargement of the myometrium.

Primary amenorrhoea

Definition. Primary amenorrhoea is defined as no spontaneous uterine bleeding by age 16 years when normal growth and secondary sexual characteristics are present, or no sexual development by age 14.

The average age of menarche is 12.7 years. The requirements for having menses are:

• a functional outflow tract and uterus

• normal ovarian hormone production and follicular development

• anterior pituitary stimulation

• hypothalamic/central nervous system regulation

Management of primary amenorrhoea

Causes of primary amenorrhoea

Hypogonadotrophic hypogonadism

Causes of hypogonadotrophic hypogonadism include physiological delay, weight loss, anorexia and excessive exercise, GnRH deficiency with anosmia, and central nervous system defects/trauma.

Investigate with the GnRH test: administer GnRH; if the LH response is appropriate, this indicates hypothalamic failure; in the absence of LH response, pituitary failure is most likely.

The commonest cause of isolated hypogonadotrophic hypogonadism due to deficient GnRH secretion is Kallman’s syndrome. This is an autosomal dominant condition, more common in males than females. There is associated anosmia secondary to defective development of the olfactory bulb and tract. Management is by ovulation induction with gonadotrophins or GnRH, and hormone replacement therapy.

Hypergonadotrophic hypogonadism (gonadal dysgenesis)

This is due to genetic or enzymatic abnormality, resulting in failure of gonadal development or abnormal functioning of the ovary.

Causes. Causes include: structural abnormalities of the X chromosome, 45XO; pure gonadal dysgenesis with 46XX, 46XY; 46XX with 17-hydroxylase deficiency (this enzyme is required for oestrogen synthesis); and other causes of premature ovarian failure (see Ch 12).

Investigations. Karyotyping is performed; as for premature ovarian failure (see Ch 12).

Management. The patient is infertile, and pregnancy can be achieved only with donor eggs and assisted reproductive techniques. For breast development, use oestrogen (ethinyloestradiol 0.01 mg or conjugated equine oestrogen 0.3 mg every second day for 6 months, then daily oestrogen for 6 months, and then the combined oral contraceptive pill).

Androgen insensitivity syndrome (testicular feminisation)

Prevalence. Prevalence is 1 in 20,000 to 1 in 64,000.

Genetics. This is an X-linked inheritance condition, so a family history is important.

Endocrinology. To use testosterone, peripheral tissues need to convert testosterone to dihydrotestosterone via the enzyme 5-alpha-reductase. Testicular feminisation is associated with a variety of defects in androgen receptors (e.g. total absence of androgen receptors, abnormal binding of androgen to receptors and postreceptor binding abnormalities).

Presentation. Primary amenorrhoea; absent uterus and ovaries; sparse pubic/axillary hair; breast development is present; inguinal hernia, possibly with testes present at hernial orifice; vaginal pouch/pit is present; tall stature.

Investigations. The karyotype is male (XY); serum testosterone is above the normal female range and is in the male range.

Management. The patient is phenotypically female; remove gonads after pubertal development (age 18–20 years) because of a risk of malignant change in the gonads. Hormone replacement therapy is required with the use of oestrogen alone. The patient is infertile with no possibility of pregnancy.

Müllerian anomalies

Presentation is one of primary amenorrhoea with secondary sexual characteristics present (see Ch 15).

Other causes of primary amenorrhoea

• hyperprolactinaemia

• polycystic ovarian disease

• agonadism

• 46XY with 17-hydroxylase deficiency

• premature ovarian failure

Constitutional delay in puberty

Definition. This is constitutional delay of growth occurring in an otherwise healthy adolescent. Height is below chronological age, but generally appropriate for bone age and stage of pubertal development, both of which are usually delayed. If the normal pattern of growth and puberty is lost, the delay in puberty is likely to be due to an endocrinological abnormality. There is delayed growth in patients with severe systemic disease (e.g. asthma, renal disease, coeliac disease, inflammatory bowel disease and long-term use of corticosteroids).

Secondary amenorrhoea

Definition. Secondary amenorrhoea is defined as no menses for over 6 months in the absence of pregnancy, lactation, hysterectomy, endometrial ablation/resection or hormonal manipulation. The definition of oligomenorrhoea varies from a cycle length of over 35 days to a woman experiencing fewer than or equal to five periods per year.

Causes of secondary amenorrhoea

Oestrogen deficiency

• gonadal failure

• hypothalamic causes (e.g. stress, exercise, anorexia)

• pituitary lesions

• hyperprolactinaemia

Unopposed oestrogen

• polycystic ovarian syndrome/chronic anovulation

• follicular cysts

• androgen excess

Other causes

• Asherman’s syndrome

• congenital adrenal hyperplasia (late-onset)

• other medical conditions (e.g. thyroid disease)

Examination

• general observations, weight, blood pressure

• sexual characteristics

• hirsutism

• galactorrhoea

• thyroid

• genital/vaginal examination

Investigations

• to exclude pregnancy

• FSH, LH

• thyroid function test, serum prolactin

• if hirsute, perform tests, including serum testosterone, DHEAS, 17-hydroxyprogesterone

• hysteroscopy/hysterosalpingogram

Management and further investigations of secondary amenorrhoea

Premature ovarian failure

(See Ch 12.)

• investigations: chromosomes, autoantibody tests

• management: hormone replacement therapy

Hypothalamic amenorrhoea

Investigations reveal normal serum prolactin levels, normal thyroid function tests, normal or low LH and FSH, and reduced oestrogen levels.

Management depends on the cause of amenorrhoea (e.g. anorexia nervosa requires psychiatric referral).

Polycystic ovarian syndrome

(See Ch 5.)

Asherman’s syndrome

• hysteroscopic resection of adhesion

• may use various means to reduce the risk of readherence of endometrial walls (e.g. oestrogen supplementation, intrauterine device)

Medical problems

• Treat and/or refer to other specialist as appropriate.

• Hyperprolactinaemia: treat with pharmacological agents or surgery.

Tumours

• Adrenals: these patients have greatly raised DHEAS and 17-hydroxyprogesterone.

• Ovarian tumours are associated with raised testosterone and androstenedione levels.

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