Chapter 3

Primary and Secondary Amenorrhoea

Amenorrhoea is the term used to describe permanent or transient absence of menstruation for a period of 6 months or more during the reproductive period of life. It is physiological before puberty, during pregnancy or lactation, and after the menopause. Occasionally, a period of 3 months is used to make the diagnosis. Amenorrhoea can be divided into primary or secondary types relative to its onset in relation to menarche, but this classification does not have a diagnostic bearing in many cases (1). They share common causes in most cases, but specific ones are also identifiable for each category.

Primary amenorrhoea

Primary amenorrhoea is a term used to indicate failure to menstruate in the following two situations:

1.  Failure to attain menarche by the age of 16 years by a female with complete or partially developed secondary female sexual characteristics;

2.   Failure to menstruate by the age of 14 years by a girl who failed to develop any secondary sexual characteristic.

It is evident that both criteria are arbitrary, and are only used to indicate a reasonable time when to start clinical and laboratory investigations. This is especially so as the age of onset of puberty is getting lower. Young girls should be investigated if menstruation failed to start 5 years after the onset of the first signs of puberty. This can be done at the age of 14 years, or even at a younger age. About 0.3% of women fail to start menstruation all together, and present with primary amenorrhoea (2). So, it is not a very common problem within a general gynaecology outpatient department. Nevertheless, it is important that all gynaecologists should have a diagnostic chart and management plan in place, especially in areas where subspecialists are not available. This is a sensitive area and both the patient and her parents will be worried about future prospects. This is especially so in cases where hyperandrogenic signs are also involved.

The most common causes of primary amenorrhoea have not changed over the years, including primary ovarian failure (48.5%), congenital absence of the uterus and vagina (16.2%), GnRH deficiency (8.3%), and constitutional delay of puberty (6.0%) (3).

Secondary amenorrhoea

Pathological secondary amenorrhoea is defined as failure to menstruate for a period of 6 months or more by a woman in her reproductive age who had menstruated previously. This is to differentiate it from the physiological type seen during pregnancy, lactation and after the menopause. Secondary amenorrhoea is almost 10 times more common than the primary type. The respective incidence of the two versions in the United States was reported as 0.3% and 3.0% respectively (2). A figure of 3.3% was quoted for secondary amenorrhoea in one Swedish study (4). Early intervention is indicated in patients who present with other associated symptoms including hyperandrogenisation, and in those who are keen to get pregnant.

General overview

It may be more practical to think of amenorrhoea as failure at one or more points along the hypothalamo-pituitary-ovarian axis, or failure of the uterus and vagina to respond to the cyclic stimulus of this axis and discharge menstrual flow in the non pregnant state. With this vision, amenorrhoea can be divided into the following categories:

• Anovulatory amenorrhoea due to HPO axis dysfunction;
• Failure of the endometrium to respond to oestrogens and progesterone;
• Failure of uterine development or genital tract obstruction;
• Other endocrine glands dysfunction.

Anovulatory amenorrhoea

This section will deal with problems related to the hypothalamus, pituitary gland and ovaries in that sequence. The detrimental effect of other dysfunctional endocrine glands on the HPO axis will be mentioned separately.

Hypothalamic amenorrhoea may be associated with many neuroendocrine changes including:

• Change in the pulsatile secretion of LH, growth hormone and prolactin;
• High plasma levels and lack of the diurnal variations of cortisol
• Delayed or absent response of gonadotrophins to GnRH stress test,
• Delayed or absent response of prolactin to thyrotrophin releasing hormone stress test;
• Abnormal thermoregulation.

The hypothalamus can be affected by direct neural or biochemical messages from other brain centres. Different methods have been used to characterise adverse hypothalamic conditions leading to disruption of GnRH pulse generation, but the following 4 subgroups are more clinically oriented

•  Functional disorders;
• Psychological or psychiatric disorders;
• Anatomical or organic disorders;
• Isolated gonadotrophins deficiency syndrome.

Functional hypothalamic disorders

Functional hypothalamic disorders indicate abnormal GnRH and gonadotrophins production, resulting in ovulatory dysfunction in the absence of any known organic, endocrine or systemic cause. Increased activation of the hypothalamo-pituitary-adrenal axis with some resistance in cortisol feedback mechanism has been suggested in women with functional hypothalamic amenorrhoea and normal body weight (5). Higher cerebrospinal fluid cortisol levels have been found in these women compared to a control group of normally menstruating women, despite having similar blood free cortisol index. The most common two causes in this category are weight related disorders, being excessive weight gain or loss, though it can also be seen in other women.

Amenorrhoea can follow anorexia nervosa and obesity whereas bulimia is associated more often with abnormal uterine bleeding and delayed menstruation, despite the fact that there is no significant weight loss. Both anorexia and obesity have a central endocrine effect. Anorexia is a psychological problem with endocrine manifestations, whereas obesity can be nutritional or may follow compulsive eating due to psychological problems. It is evident that both conditions can come under the psychological subheading as well. Anorexic women become amenorrhoeic even before they become unduly thin, which emphasises the psychiatric role in such cases. This is different with simple nutritional weight loss which does not fulfil the same psychiatric criteria as anorexia. In these cases, women can become amenorrhoeic mostly after going below a certain critical BMI specific for each individual. Furthermore, they usually regain some menstrual function as soon as they approach that BMI, unlike patients with anorexia who may regain a lot of weight yet remain amenorrhoeic. Nutritional obesity can cause loss of menstrual function through different mechanisms, not involving a psychiatric component. This can be affected through disturbed prolactin secretion and increased brain endorphins, dopamine, and opioids. There is also reduction in the hepatic production of SHBG, which can lead to increased levels of free androgens which are converted to oestrone by peripheral fat. All these factors can affect the hypothalamus negatively to different degrees, reduce GnRH pulse generation, and lead to disturbed gonadotrophins secretion. Loss of weight should be the priority to reactivate the HPO axis, rather than induction of ovulation. Some menstrual activity can be expected after losing 10% of the body weight by some obese patients.

Exercise induced amenorrhoea also falls under this diagnostic subgroup. These patients usually have the triad of amenorrhoea, eating disorders, and osteoporosis. Excessive competitive exercise is usually associated with increase in stress hormones mainly ACTH and cortisol which have direct effect on the hypothalamus, reducing GnRH pulse frequency. They also have direct effect on the pituitary gonadotrophs making them less responsive to the GnRH pulses. This is compounded by the fact that there is a high incidence of eating disorders in athlete women (6). Different rates of amenorrhoea have been reported with different types of exercise. Furthermore, pubertal girls are more prone to develop amenorrhoea than older women. Rates of 5 - 66% had been noted with competitive athletes and 19 - 44% with ballet dancers.

Drug induced hypothalamic dysfunction can follow prescribed medication or misuse of recreational drugs. Most of them affect brain neurotramitters, and interfere with the proper functioning of the hypothalamic nuclei. Normally, GnRH secretion is affected by norepinephrine, dopamine, serotonin, acetylcholine, endorphins, enkaphalins, glutamate and aspartate. Any drugs which affect these neurotramitters will modulate GnRH pulse generation and consequently gonadotrophins secretion. Increased brain opiates activity can lead to hypothalamic inhibition and amenorrhoea, which can be reversed by prolonged use of opiates receptors antagonists like naltrexone. Such medication was found to counteract the inhibition of GnRH pulse generation in these cases (7).

The role of depoprovera in causing amenorrhoea will be singled out in this chapter, as it is becoming more popular as a long acting contraceptive and for the treatment of endometriosis. It is debo-medroxyprogesterone acetate which is given by deep intramuscular injections every 3 months. As a potent progestogen, it directly affects the hypothalamus reducing GnRH pulse frequency and hence reduces gonadotrophins secretion. It can induce amenorrhoea for variable periods of time after repeated injections. Almost 50-70% of women will have long periods of amenorrhea after using depoprovera for one year or more. It may take up to 18 months before regular ovulation is resumed following the last injection, though return of fertility has been quoted to occur 9 months after the last injection (8). Other side effects include irregular uterine bleeding, functional ovarian cysts, and osteoporosis. Accordingly, patients should be made aware of these side effects, before committing themselves to this medication. Other drugs in common use which can cause amenorrhoea include high doses of corticosteroids, isoniazid, and danazol which is a synthetic 2, 3 isoxazole derivative of 17a-ethinyl testosterone.

Psychological and psychiatric hypothalamic anovulation

Patients with severe and protracted anxiety states and depression are liable to have menstrual irregularities including amenorrhoea. Short term stressful conditions may not have an adverse effect on the hypothalamus, but prolonged periods of stress or depression can affect the brain neurotramitters. This is especially so for corticotrophin releasing hormone which is an important neurotransmitter and can interfere with GnRH pulse generation. This is affected through an increased central opioids activity, as it can be suppressed by the opioids antagonist naloxone (9). On the other hand, the effect of short term tress depends on the stage of the menstrual cycle and oestrogen level. It could stimulate premature LH release during the second half of the cycle, or inhibit follicular growth if it occurred during the early follicular phase (10). Both effects could be detrimental to the normal process of ovulation.

Depressed patients are more liable to develop hypothalamic amenorrhoea due to increased concentration of opioids and dopamine in the brain. Evidence of involvement of both chemicals in causing hypogonadotropic amenorrhoea has been known since 1980 (11). Treatment with antidepressants and anxiolytics can also affect hypothalamic function. Accordingly, it is important to check for any medication a patient may be using during the clinical interview. Further information should be sought from the patient’s primary care doctor, when in doubt. Increased blood levels of cortisol due to increased pulse amplitude, and decreased levels of DHEA-S have been reported in women with psychogenic amenorrhoea, compared to women with normal cycles. Furthermore, loss of cortisol circadian rhythm and early escape from dexamethasone suppression have been reported in depressed patients by Sacha et al in 1973 (12) and Amsterdam et al in 1983 (13) respectively. On the other hand, major affective disorders have also been reported in many amenorrhoeic runners, or in their first or second degree cousins (6).

Anatomical hypothalamic causes of amenorrhoea

Anatomical hypothalamic lesions are not common but can interfere with the hypothalamic brain connections, obstruct the pituitary stalk, or even damage the sella turcica itself with the enclosed pituitary gland. The most important and well known tumours are craniopharyngiomas. Patients may present with amenorrhoea and very high prolactin levels, due to interruption of the pituitary stalk. Involvement of the optic chiasm and optic nerves can lead to visual symptoms.

Other intracranial tumours not involving the hypothalamus include gliomas and astrocytomas which can affect the brain connections with the hypothalamus. Pituitary tumours will be considered separately in this chapter. It is important to conduct a proper neurological examination, including the optic discs and visual fields. This is especially important in patients with neurological symptoms, high prolactin levels, and those with precocious isosexual puberty.

Isolated gonadotrophins deficiency syndrome is not common, and patients usually fail to develop secondary sexual characteristics. They are usually tall and eunuchoid with long arms and legs bones and longer arms span than height. Development of the axillary and pubic hair may be normal, as the adrenocorticotrophic axis is normal. Many patients may have defective sense of smell, as in Kallmann’s syndrome, due to abnormal development of the olfactory bulbs. Failure of migration of the GnRH neurons from the embryonic olfactory placode into the brain during fetal life, or lack of establishment of a functional connection with the hypophyseal portal system may account for the hypogonadotropic state in patients with Kallmann’s syndrome (14).

Pituitary causes of amenorrhoea

Failure of the pituitary gland to produce gonadotrophins can be a primary problem within the pituitary gland itself, or can be secondary to failure of stimulation by GnRH. It can be an isolated gonadotrophins deficiency, but panhypopituitarism can also be seen. Patients with hypopituitarism can be deficient in growth, thyroid and adrenal hormones. They can present with amenorrhoea, as well as symptoms related to other hormonal deficiencies. Such symptoms include easy fatigability, cold intolerance, weakness and loss of axillary and pubic hair. Failure of pubertal girls to grow is an important sign which indicates neurological testing and MRI examination of the brain.  Hypopituitarism can follow any of the following conditions:

• Non functioning pituitary tumours;
• Pituitary infarction;
•  Empty sella syndrome;
• Sheehan syndrome following postpartum haemorrhage;
• Pituitary granulomas including tuberculosis and histiocytosis X;
• Head injury can lead to damage of the pituitary gland, with partial or total loss of endocrine function. Severe loss of ACTH may lead to shock due to loss of adrenal hormones. On the other hand, symptoms related to gonadotrophins loss can be delayed and may show after some time, depending on the degree of cellular damage.

Ovarian causes of amenorrhoea

Direct ovarian or gonadal causes are related more often to primary amenorrhoea, and premature ovarian failure with secondary amenorrhoea. At the same time, chromosomal abnormalities are more likely to be the cause the younger the patients are. The following gonadal causes are more likely to be seen within this group:

Gonadal dysgenesis

Gonadal dysgenesis is the term used to describe atresia of gonadal germ cells leading to streak gonads. Development of the ovaries has been described in some detail in the previous chapter. Patients with gonadal dysgenesis or streak gonads can have 46XX, 46XY, 45XO, or different combinations of these chromosomes. Development of the primitive gonad into a testicle depends on the presence of the sex determining region gene (SRY) on the short arm of the Y chromosome. Total absence of this gene in a 46XX fetus allows development of the primitive gonads into ovaries in females. Mutations in the SRY gene account for 20-30% of Swyer Syndrome cases with 46XY pure gonadal dysgenesis. Most cases may follow mutations in other genes necessary for the normal development of the testicles (15). In such cases, failure of the testicles to develop leads to failure of testosterone and antimullerian factor production. Accordingly, no internal or external male genital organs develop, and the mullerian ducts progress into full internal female genitals instead. The urogenital sinus also fails to masculine, and develops into a vulva and lower vagina. Adequate pubic and axillary hair growth is stimulated by adrenal androgens at puberty. Most cases of Swyer syndrome are sporadic, but exceptionally familial cases are seen in women with complete or partial gonadal dysgenesis, in an autosomal recessive manner (16). Pure gonadal dysgenesis, with 46XX or 46XY chromosomes, is usually associated with female hypogonadism with high FSH levels and primary amenorrhoea. Patients with mixed gonadal dysgenesis and chromosomal combinations may have one streak gonad on one side, plus a testicle or germ cell tumour on the other side. A good example for such asymmetrical gonadal development is seen in 45XO / 46XY mosaics. On the other hand, some patients may have more than one cell line in different tissues, with normal development of secondary female sexual characteristics, yet they develop primary ovarian failure in their 20s or early 30s. In one such case peripheral karyotyping was normal, yet an abnormal cell line was found at the ovaries by Abdel-Gadir and Ramadan in 1990 (17). Women with triple X chromosomes syndrome can also present with secondary amenorrhoea. They usually have normal secondary female sexual characteristics, and are able to have children. They are also liable to have tall stature and lower IQ than women with 46XX chromosomes. This can show as delayed speech and learning difficulties. About 10% of affected females have kidney abnormalities or seizures. It has been estimated that 1 in 1000 newborn girls have triple X chromosomes. In most cases, this usually follows random nondisjunction during oocytes division and is not inherited from parents. The level of physical and functional changes usually relates to the number of affected cell lines, as patients with 46XX / 47XXX mosaicism have been described. To conclude this subsection, it is important to mention that the most common chromosomal aberration in patients with gonadal dysgenesis is 45XO or Turner’s syndrome. The diagnosis can be suspected in these cases from the characteristic somatic phenotype, even before peripheral karyotyping is analysed.

Fragile X syndrome will be considered separately in this section. Carriers of the permutations of the familial mental retardation gene (FMR1) which is located in the long arm of the X chromosomes (Xq27) have 50-200 repeats of the cytosine-guanine-guanine trinucleotide in the gene, instead of the normal rate of 5-50 repeats. They have 20% chance of developing primary ovarian failure. It was diagnosed in 6% of women with premature ovarian failure and normal 46XX chromosomes (18; 19). This percentage reached 14% in cases with similar family history (19). Affected patients may not show any mental or somatic signs of the syndrome. Family history of mental disability can be elicited more commonly in male siblings. There is a 50% chance that each offspring of a female carrier inherits the gene permutation. Somatic characteristics include a long face, prominent ears, high arched palate, hyper-extensible finger joints, double jointed thumbs and flat feet. There is no specific treatment for this condition. This diagnosis should be confirmed by chromosomal testing for FMR1.

Few enzymatic and receptor signal defects have been described as causes of both primary and secondary amenorrhoea depending on the degree and severity of the condition. Gene mutation of the FSH receptor which is a member of the G-protein-coupled-receptors group can cause streak gonads and primary amenorrhea, when present in the most severe form. Lesser variants may lead to arrest of follicular development at different stages, ranging from antral to the later stages of development. This may be associated with some degree of secondary sexual characteristics development and early secondary amenorrhoea. More information about other mutations can be found in Chapter 10.

Ovarian irradiation and chemotherapy

Pelvic irradiation and use of chemotherapeutic agents for malignant conditions can lead to damage of the germ cells within the ovaries, with subsequent ovarian failure and hypergonadotropic amenorrhoea. The older the woman is at the time of exposure, the more chance she will develop irreversible ovarian damage. Transposition of the ovaries during radiation can help in saving ovarian function. It is estimated that 800 rads exposure leads to permanent ovarian failure irrespective of the age group. Lower doses may be associated with partial or complete recovery in younger patients. It is current practice that most young women with breast cancer receive adjuvant cytotoxic chemotherapy, as well as hormonal treatment for oestrogen receptor-positive tumours. This brought the issue of preservation of later fertility potential to light. The older the patient at the time of treatment, the higher the chance she will have permanent amenorrhoea after chemotherapy. Rates of 21-71% and 49-100% have been quoted for women younger and older than 40 years (20). However, these wide variations in incidence are most likely related to the type of drug and dosage used as reported by Minton and Munster in 2002 (21).

Ovarian tumours

Hormonally active ovarian tumours can lead to long periods of amenorrhoea depending on the type of hormone produced by the tumour cells. The list is long and includes granulosa cell tumours, fibrothecomas, ßhCG producing teratomas, and androgen producing tumours. A recent case report of 8 years secondary amenorrhoea caused by a parasitic ovarian leiomyoma which produced high levels of inhibin B has been documented by Abdel-Gadir et al in 2010 (22). The patient resumed regular menstruation one month after removing the mass. In all these cases pelvic ultrasound scanning can show an ovarian mass, and a blood hormonal profile may reveal the nature of the chemicals produced

Genital anatomical factors

The first 4 subheadings shown below have already been covered in chapter 2. They all cause primary amenorrhoea, and should be considered early, especially in women with cyclic pelvic pain and menstrual-like symptoms. The last subheading, which is a cause of secondary amenorrhoea or hypomenorrhoea, will be addressed in this chapter.

·       Imperforate hymen;

·       Transverse vaginal septum;

·       Partial or complete mullerian agenesis;

·       Vaginal agenesis involving the urogenital sinus part of the vagina;

·       Endometrial damage.

Traumatic amenorrhoea may follow endometrial damage subsequent to uterine surgery or infections. It can follow dilatation and curettage, termination of pregnancy, caesarean section, myomectomy, and manual removal of the placenta. An underlying pregnancy is involved in most cases. All these procedures can lead to complete or partial obstruction of the uterine cavity with adhesions, depending on the degree of endometrial destruction. Nonetheless, minimal adhesions may be associated with total damage of the basal endometrial layer leading to amenorrhoea, not responsive to any hormonal treatment or surgical correction. This pattern may also be seen with tuberculosis infection of the endometrium, leading to failure of endometrial growth and shedding in response to the rise and fall of oestrogen and progesterone during a menstrual cycle. On the other hand apical adhesions covering the lower part of the uterus may cause amenorrhoea without any significant damage to the endometrium. This may follow a caesarean section, as shown in figure number 5.

Previous history of uterine surgery is the main clue to a proper diagnosis in this group of women presenting with hypomenorrhoea or secondary amenorrhoea. Ultrasound scan examinations and saline infusion sonohysterography may give some clues to the site and extent of intrauterine adhesions.

Other endocrine dysfunctions

Functional integrity of the HPO axis may be adversely affected even by the most subtle changes in other pituitary or target endocrine glands hormones.  The correlated problems we most see as gynaecologists are associated to:

·       Thyroid gland dysfunction;

·       Hyperprolactinaemia;

·       Adrenal gland dysfunction;

·       Polycystic ovary syndrome (PCOS).

Thyroid dysfunction 

Thyroid gland disorders are very common in women, and may cause different types of menstrual irregularities. Accordingly, a high degree of suspicion should be exercised. This is especially so when dealing with women >40 years old, and younger ones with similar family history. The function of the HPO axis is closely interlinked to that of the thyroid gland. Both, an underactive or overactive thyroid gland may affect ovulation by different means. TSH and gonadotrophins are glycoproteins with very similar structure. They even have identical amino acids sequence in their alpha chains. In vitro studies showed that thyroid hormones increased granulosa cells division, and enhanced their production of oestradiol. This was more noticeable for T3 than T4 (23). On the other hand, any change in the level of circulating oestrogens can also affect the thyroid gland. High oestradiol blood levels stimulate the liver to produce more thyroxine binding globulin which is the carrier molecule of thyroxine. Normally this leads to a drop in the level of free T4, calling on the thyroid gland to produce more thyroxine to compensate for that effect. This can be seen during pregnancy, or after exogenous administration of oestrogens including the combined contraceptive pills, and hormone replacement therapy.

Childhood hypothyroidism may lead to delayed or precocious puberty, as discussed in Chapter 2. In the later case, secondary stimulation of the pituitary gland by TRH increases gonadotrophins production. Elevation of TRH can also lead to hyperprolactinaemia, and affects the HPO axis adversely. There is also reduced production of SHBG in cases of hypothyroidism, which leads to increased levels of free testosterone and oestradiol in circulation. High free androgens are converted to oestrone in the hypothalamus which can modulate GnRH generation. Nonetheless, gonadotrophins levels may be normal, but a blunted or delayed response of LH to GnRH stimulation may be seen in patients with hypothyroidism (24; 25)

On the other hand, high thyroxine levels increase the pituitary gonadotrophs sensitivity to GnRH with significant increase in the production and secretion of LH during both phases of the cycle. A similar effect has been reported for FSH, but not by all investigators. This effect may be sustained for up to 4 months after initiating antithyroid treatment, which explains the lag period between normalisation of thyroid indices and resumption of normal ovulatory function. High thyroxine blood levels also increase the production of SHBG by the liver which reduces the metabolic clearance of oestradiol. There is also increased production of oestradiol by the granulosa cells in response to thyroxine (22). Accordingly, there is 2-3 folds increase in oestradiol level during the follicular and luteal phases of the cycle. There is also increased production of testosterone and androstenedione, with significant increase in their conversion rates to oestradiol and oestrone respectively. Even with regular menstrual cycles, progesterone levels during the luteal phase were found to be low in women with hyperthyroidism compared to control groups.

Hyperprolactinaemia 

Circulating human prolactin can be found in 3 different molecular weights of 23, 60 and 100 kilodaltons. They are called little, big and big-big prolactin respectively. The major circulating form is little prolactin which is also the biologically active hormone. The big-big variety is known as macroprolactin (26), and is made of little prolactin and immunoglobulin G antibody. This complex structure interferes with the hormone/receptor interaction (27) and renders prolactin biologically inactive. Macroprolactinaemia may be found in 18-42% of patients with high prolactin blood levels (28). These patients are usually asymptomatic and have regular menstrual cycles, as the hormone is biologically inactive. Recently, a suggestion has been made to test the biological activity of prolactin in all patients with hyperprolactinaemia, as this may affect the management plan (29). This practice is not yet universal and symptomatic patients with hyperprolactinaemia are treated accordingly. The rest of the text in this section relates to the biologically active prolactin.

About 15% of amenorrhoeic women have increased prolactin blood levels, which can affect the HPO axis directly at all levels. Increased prolactin production can follow any of the following conditions:

·     Prolactin producing pituitary tumours may be micro or macroadenomas, with <10 mm and >10 mm size respectively. Such tumours are usually autonomous, and the amount of prolactin produced depends on their size. They should be excluded with MRI during investigations of hyperprolactinaemia.

·     Certain drugs functionally block the inhibitory effect of dopamine on the pituitary gland lactotrophs, allowing autonomous production and release of prolactin. Oestrogens have been shown to restrict access of dopamine into the lactotrophs granules. This explains the exaggerated prolactin response after TRH stimulation test following oestrogen medication.

·     Traumatic stalk transection or disruption of the vascular connections between the hypothalamus and pituitary gland by a craniopharyngioma, pituitary tumour, or any other intracranial growth can prevent delivery of prolactin inhibitory factor to the pituitary gland.

·     Increased production of prolactin by the pituitary gland may follow increased production of TRH due to hypothyroidism. It can also follow the use of such drugs as metoclopramide and cimetidine which act as dopamine antagonists, and allow more prolactin secretion by the pituitary gland. This effect can also be augmented by prior exposure to oestrogen medication. It is interesting that the effect of cimetidine on prolactin secretion is blunted in patients with hyperthyroidism (30). This may be an indication that cimetidine affects prolactin secretion by more than one means. Chronic oestrogen medication can also enhance prolactin secretion, in isolation, by increasing lactotrophs mitotic activity and number. Other conditions which can increase prolactin secretion include nipples manipulation, chest surgery, herpetic inflammation of the intercostal nerves and renal failure.

·     Hypothalamic dopamine deficiency may follow inflammatory brain condition such as sarcoidosis, arteriovenous malformations and medical treatment with drugs such as reserpine and alpha methyldopa.

Hyperprolactinaemia can alter GnRH pulse generation, and ultimately reduce gonadotrophins production, mainly LH. Alteration or abolition of the LH surge may lead to inadequate ovulation, abnormal luteal phase, polymenorrhoea, polymenorrhagia and menorrhagia. Pituitary adenomas and craniopharyngioma are more likely to cause amenorrhoea, as they lead to very high prolactin levels with severe gonadotrophins deficiency and hypoestrogenic state. Moderate elevation in prolactin levels following hypothyroidism or drug medication can cause oligomenorrhoea and abnormal uterine bleeding in some patients, but may also cause amenorrhoea. It may also act directly at the ovaries and reduce the effect of gonadotrophins on the follicles at a post-receptor level. This can lead to inappropriate folliculogenesis, long follicular phase and abnormal ovulation. Low luteal phase serum progesterone may also follow an abnormal effect at post LH receptors level. The clinical effects of hyperprolactinaemia can be summarised as follows:

­ Dopamine ® ¯ gonadotrophins production ® ¯ follicular stimulation ®  ¯ steroidogensis ® ¯ oestradiol ® ¯ positive feedback mechanism ® ¯ LH surge ® anovulation/oligomenorrhoea  ® amenorrhoea

High prolactin levels can also interfere with adrenal enzymatic activity leading to increased production of androgens, which have detrimental effects on the ovaries and endometrium. Changes in 3β-hydrtoxysteroid dehydrogenase activity may reduce the conversion of ∆5 precursors into ∆4 products. This leads to increased production of 17a-hydroxypregnenolone and DHEA-S, with the later precursor changed into more potent androgens in peripheral tissues. It is not usual for an isolated mild deficiency of this enzyme to cause total amenorrhoea. Patients are more likely to present with some hyperandrogenic symptoms and signs.

Adrenal gland dysfunction 

Detailed information about the adrenal hormones can be found in Chapter 4. In the context of amenorrhoea, women with adrenal dysfunction can fall into 2 major groups

1.    Enzymatic deficiencies which are autosomal recessive problems;

2.    Cushing’s syndrome which is a rare presentation in the gynaecology clinic.

The lack of a strong evidence associating adrenarche to the onset of puberty in normal girls has been discussed in Chapter 2. Nonetheless, excessive production of adrenal androgens due to 21-hydroxylase deficiency may lead to precocious puberty. Severe untreated conditions can result in primary or secondary amenorrhoea due to the effects of very high androgens at different parts of the HPO axis, and the uterus. Women with 21-hydroxylase deficiency are more prone to develop secondary polycystic ovaries. They may also show signs of hyperandrogenisation including acne and excessive hair growth. The less common 11-hydroxylase deficiency may cause similar problems, with an occasional added risk of high blood pressure. Deficiency of 17a-hydroxylase occurs in 1: 50,000 to 1: 100,000 newborns (31). It usually occurs in combination with 17/20 lyase enzymatic deficiency, as they are controlled by the same cytochrome P450c17 enzyme. Nonetheless, they might occur separately depending on the type of mutation (32). It has more dramatic effects than the other two enzymatic deficiencies mentioned before. Deficiency of 17a-hydroxylase reduces or even totally blocks the conversion of progesterone to 17a-hydroxyprogesterone, and pregnenolone to 17a-hydroxypregnenolone. With reduced synthesis of 17a-hydroxyprogesterone, less 11-deoxycortisol and cortisol will be produced. Deficiency of 17/20 lyase enzymatic activity will compound matters further by reducing the conversion of the available 17a-hydroxyprogesterone and 17a-hydroxypregnenolone to androgens, which are the substrates for oestrogens. The ultimate clinical outcome of these changes will be:

·     Failure of cortisol production will lead to increased production of ACTH, with excessive stimulation of the adrenal gland and further accumulation of the pre-block precursors. Excessive progesterone will be converted more readily to deoxycorticosterone and corticosterone. This may lead to hypertension and hypokalaemic alkalosis. The age of onset and degree of severity of hypertension vary between the affected individuals (33)

·     Failure to produce androgens and oestrogens will result in failure to develop secondary sexual characteristics, and primary amenorrhoea.

The biochemical picture will be high levels of FSH, LH, progesterone, deoxycorticosterone and corticosterone, but low oestradiol level. Aldosterone and plasma rennin activity may also be reduced. The ovaries may show multicystic pattern, but ovarian biopsies showed no evidence of follicular maturation. Despite failure of spontaneous follicular growth, patients with 17a-hydroxylase (34) and isolated 17/20 lyase (35) enzymatic deficiencies had positive response to exogenous gonadotrophins stimulation with adequate follicular growth, oocyte maturation and fertilisation during in vitro fertilisation programmes. These studies demonstrated the need for a proper diagnosis to differentiate these patients from others with high FSH and low oestradiol levels due to primary ovarian failure.

Individuals with 46XY karyotyping and severe or homozygous 17b-hydroxysteroid dehydrogenase 3 mutations may be born with external female genitals, and are raised as females. They will fail to menstruate, and develop hyperandrogenic habitat at the time of puberty. This topic will be discussed in more details in Chapter 4.

Cushing’s syndrome is usually diagnosed in a medical department rather than a gynaecology clinic. The main endocrine problems are excessive ACTH induced, or independent cortisol production by the adrenal glands. There is also loss of the cortisol circadian rhythm, together with the hypothalamo-pituitary-adrenal negative feedback mechanism. The clinical manifestations may be subtle in the early stages and many of the symptoms are shared by other endocrine dysfunctional conditions. The full blown picture may show central obesity, purple wide striae, hyperandrogenisation, facial plethora, mooning of the face, muscle wasting, diabetes and high blood pressure. Patients may also present with secondary amenorrhoea, even at the early stages of the syndrome. Accordingly, it should be kept in mind during the investigations of patients who present with amenorrhoea associated with any of the other symptoms or signs described before. It is important not to confuse this condition with the pseudo Cushing state related to excessive alcohol abuse and depression. These patients present with clinical and biochemical changes reminiscent of Cushing’ syndrome. They may even fail to respond to a dexamethasone suppression test. Treatment is different in these cases, and should only target the two underlying problems.

Polycystic ovary syndrome

This is the most common female endocrine disorder and has been reported in 3.5-11.2% of all women. Almost 50% of all female endocrine problems are related to PCOS. The spectrum of symptoms includes hyperandrogenisation., anovulation, obesity, and infertility. Menstrual dysfunction is variable, with oligomenorrhoea being most common, but primary and secondary amenorrhoea may be seen. A new consensus has been agreed for the diagnosis of PCOS in 2003 (36), but still needs to gain universal approval. The Rotterdam expert group stated that PCOS is an ovarian dysfunctional condition characterised by hyperandrogenism, anovulation and the presence of 12 cystic areas in one or both ovaries. Other causes of hyperandrogenic states should be excluded first, before making the diagnosis. A more detailed account will be given about PCOS in Chapter 6.

Management of amenorrhoea

Thorough medical history should be taken and physical examination and investigations should be performed according to the patient’s age, pubertal development, general phenotype and the presence or absence of other endocrine physical signs. The main objectives should be to exclude medical problems which can affect the patient’s general health. This is especially so for intracranial, ovarian or adrenal tumours. The management plan ought to have purposeful treatment oriented objectives. It must seek to distinguish between the following conditions:

1.    Hypogonadotropic hypogonadism;

2.    Hypergonadotropic amenorrhoea with or without gonadal dysgenesis;

3.    Hyperandrogenic amenorrhoea;

4.    Anatomical amenorrhoea.

The following action plan is suitable for most patients, and can be modified as necessary to suit each individual case:

·       Personal biodata including weight, height, arms span and blood pressure should be recorded.

·       Tanner’s breast and pubic hair staging should be performed.

·       Look for hyperandrogenic signs, central obesity, and purple wide striae.

·       Signs of hypo or hyperactive thyroid gland should be ascertained.

·       The vulva should be inspected in cases of primary amenorrhoea.

·       Digital vulvar examination of sexually active patients with primary amenorrhoea should be done.

·       Neurological examination including the optic discs and visual fields should be conducted.

·     Transabdominal and transvaginal ultrasound pelvic scan examinations may show the presence or absence of the uterus and ovaries. Distension of the uterus and vagina with blood may be demonstrated in cases of haematometra and haematocolpos, secondary to genital tract obstruction. These are the findings mostly seen in younger patients. Few women with amenorrhoea or dysfunctional uterine bleeding may show polycystic ovaries and the endometrium may be hyperplastic and thick. This is a pattern seen more often in obese women as shown in figure 6.

Intrauterine adhesions can show in many different ways including a thin endometrium with bright neighbouring echoes, as shown in figure 6. Loss of the endometrial / myometrial interphase may be the only ultrasonic finding. This could be more discernable during the luteal phase of the cycle because of the contrast between the remaining part of the echogenic secretory endometrium and the normally hypoechoic inner part of the myometrium. The diagnosis is best concluded with saline infusion sonohysterography. Failure of uterine distension may indicate total obliteration of the cavity. Alternatively, distortions of the cavity with echogenic bridges, or failure of a specific part of the cavity to distend with saline may be seen. Saline infusion sonohysterography is an outpatient procedure which can be used in isolation in most cases, or in conjunction with office hysteroscopy. It should be performed under aseptic conditions, and should be covered with antibiotics.

Figure 8 shows an indiscriminate endometrial / myometrial interface, marked by an arrow head, which proved to be due to intrauterine adhesions as shown by saline infusion sonohysterography in Figure 9. The intact part of the cavity is revealed by the hypoechoic saline with adhesions shown as bright bridges dividing the cavity. The catheter used for saline infusion is shown as two bright parallel lines in the cervical canal.

·       MRI of the pituitary gland and brain are necessary in cases of hyperprolactinaemia, and in cases of delayed and precocious isosexual puberty. This is especially important in patients with neurological symptoms, or abnormal findings on neurological examination. Plain skull X-ray examinations are not sensitive enough to be used for this purpose.

·       Peripheral karyotyping is important in cases of primary or secondary amenorrhoea with high FSH blood levels. It is also useful in cases of suspected androgen receptor insensitivity (46XY) and Mayer-Rokitansky-Küster-Haϋser’s syndrome (46XX).

·     X-ray of the left hand and wrist for bone age should be requested for women with delayed or precocious puberty, and the film compared to a standard atlas.

·       An endocrine profile should be requested including:

o   FSH, LH, and oestradiol can differentiate between hypo and hypergonadotropic amenorrhoea;

o   TSH and free T4 are needed to investigate thyroid function.

o   Testosterone, androstenedione and SHBG are useful in cases of hyperandrogenic amenorrhoea and in cases suspected of androgen insensitivity syndrome. Very high testosterone levels may point towards ovarian or adrenal tumours.

o   17-hydroxyprogesterone is the main precursor necessary for the diagnosis of 21-hydroxylase deficiency.

o   DHEA-S, androstenedione and cortisol should be assessed, as necessary, to give more information about the adrenal gland. Very high DHEA-S may indicate the presence of an adrenal tumour.

·     Pituitary dynamic tests for FSH, LH, TSH, ACTH and growth hormone can be performed to test the integrity of all trophic hormones in cases suspected of hypopituitarism.

·     Stimulation of the adrenal gland with a bolus dose of synacthen should be utilised to diagnose 21-hydroxylase enzymatic deficiency in marginal or doubtful cases. Excessive increase in the level of 17-hydroxyprogesterone will confirm the diagnosis. A similar test is also available for the less common 11β-hydroxylase deficiency with metyrapone.

Treatment of primary and secondary amenorrhoea

The main objective of managing patients with amenorrhoea is to exclude serious organic causes which may affect their future wellbeing. Identifying patients with hypo or hypergonadotrophic amenorrhoea is the next important objective. It is also important to remember that endocrine glands are biochemically interlinked, and a derangement in one gland may affect many others. Accordingly, the diagnostic workup should be thorough and purposeful to detect such changes. A good example is the elevation of prolactin level in response to hypothyroidism. Treating hyperprolactinaemia in such cases entails dealing with the causative hypothyroidism first. Management of amenorrhoeic patients in general depends on the patient’s age, definitive diagnosis, associated symptoms and fertility demands as shown in the following examples:

·     Development of young hypogonadal pubertal girls should be enhanced with small doses of oestrogen to allow linear growth and development of secondary sexual characteristics. The dose should be maintained and a progestogen should be added to allow regular endometrial shedding, once the patient is fully developed. This will also allow the normal attainment of maximum bone density by the age of 20 years, and prevent osteoporosis. Dysgenetic gonads should be removed in individuals with a Y chromosome, to guard against malignant transformation. Induction of ovulation with gonadotrophins is the standard treatment in patients with hypogonadotropic hypogonadism, when pregnancy is desired. Pulsatile GnRH medication is also possible in cases of hypothalamic amenorrhoea with an intact pituitary gland.

·     Patients with hyperprolactinaemia usually respond well to bromocripine which is a dopamine D1 and D1 receptor agonist. It should be started in a small dose of 2.5 mg every day with food. The dose should be increased slowly over few days and titrated against prolactin level. A positive response of 80% is expected in cases of amenorrhoea caused by hyperprolactinaemia. Some menstrual activity may resume after a short period of time, but it usually takes many weeks or months before a full ovulatory response is seen. Accordingly, additional medication to stimulate ovulation should not be rushed. Bromocripine is indicated even in cases of pituitary macroadenoma as a first line of management. The tumour size may shrink, which makes it easier to remove surgically. Tumours which already involved neighbouring structures, especially the optic chiasm need surgical decompression first. Regular follow up with MRI and visual field examinations should also be done together with serial estimations of prolactin blood levels. There is a risk of pituitary tumours increasing in size during pregnancy. Longer acting dopamine agonists are available if bromocripine is not well tolerated, and for maintenance purpose for long periods of time in patients who are not keen to get pregnant. Single weekly doses of cabergoline (dostinex 0.5 - 1.0 mg) can improve compliance with taking the drug.

·     Patients with hypo and hyperthyroidism should be managed accordingly. Thyroxin treatment should be started with a small dose and built up against TSH levels, to reduce side effects especially cardiac ones. It is important to remember that menstrual function and more importantly regular ovulation may take much longer time to resume after correction of the peripheral blood levels of thyroid indices. Similarly, other medications to induce ovulation should not be rushed. The relationship between hypothyroidism and hyperprolactinaemia has been mentioned before.

·     Eating disorders are common in young women, and should be treated as psychological rather than endocrine problems. These patients usually have negative body image, and intense fear of gaining weight. They may also suffer from depression, anxiety and obsessive compulsive disorders. Treatment should focus on cognitive behavioural therapy and behaviour modification, personal and family counselling, nutritional advice, as well as individual and group counselling sessions. Antidepressants and hormone replacement therapy should be prescribed in severe cases suffering from depression, and to prevent bone loss respectively.

·      A diagnosis of hypothalamic dysfunction is usually made in amenorrhoeic patients with normal gonadotrophins, oestrogens, prolactin, thyroid indices and adrenal hormones. This is fitting with the WHO group 2 classification of amenorrhoea. Patient with PCOS can show clinical and / or biochemical hyperandrogenisation. Treatment is almost the same in both groups depending on the following parameters as far as menstruation is concerned:

1.  Patients who are not keen to get pregnant should have regular progestogens withdrawal bleeding every 6-8 weeks, to prevent endometrial hyperplasia. Alternatively, they can be offered an oral contraceptive pill to have monthly withdrawal bleeding, and prevent unwanted pregnancies at the same time.

2.  Patients who wish to conceive should be offered induction of ovulation with clomiphene citrate as a first choice. Gonadotrophins injections can be used when a good response is not attainable. They are more expensive, and need expert serial monitoring to reduce the risk of excessive response and hyperstimulation.

Summary

It is evident that primary and secondary amenorrhoea share many similar causes, and fit into almost identical management strategies. A logical clinical, hormonal and imaging approach will elucidate most cases with minimal need for advanced investigations. The sensitivity of the problem especially with primary amenorrhoea in young pubertal girls and in older patients who wish to get pregnant makes it necessary for all gynaecologists to have a clear management plan, as stated before. Dealing with the anatomical abnormalities involved with primary amenorrhoea can pose greater difficulty, and liaison with a gynaecologist experienced in this form of surgery is important. As a whole, a multidisciplinary approach will be needed to cover the different needs of these patients.

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