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An oestrogen-progestin challenge, administered using combined oral contraceptive pills, is one of the ways of investigating the cause of secondary amenorrhoea. — TNS

Do you keep missing your period?

When a woman passes menarche (her first period) and does not menstruate for at least six months, it is called secondary amenorrhoea.

Secondary amenorrhoea is commonly caused by pregnancy, lactation and menopause. Approximately 2% to 5% of women suffer secondary amenorrhoea from all other causes. Structural causes include damage to the endometrium (Asher-man syndrome) and obstruction of the outflow tract (cervical stenosis).

Hormonal causes include pregnancy, lactation, thyroid dysfunction, hyperprolactinaemia, hyperandrogenism (including polycystic ovarian syndrome or PCOS), hypogonadotropic hypogonadism (hypothalamic-pituitary dysfunction), and suppression of the endometrium by hormonal birth control.

History and examination

A doctor will first consider a patient’s medical history. Ascertaining the birth control method the patient is using is crucial, as progestin-containing contraceptives (such as combined oral contraceptives) can suppress endometrial growth.

A history of infrequent, irregular periods is also important, e.g. does the patient have a history of anovulation (where no ovum is released from the ovary during the menstrual cycle), or was the amenorrhoea sudden?

Has there been a previous inciting event before onset of secondary amenorrhoea, such as childbirth, surgery, trauma or pelvic infection?

If the patient exhibits headaches, vision changes or galactorrhoea (milky discharge from the nipples not caused by childbirth), they may have hyperprolactinaemia (excessive production of prolactin, the hormone responsible for milk production in women) from a (benign) pituitary prolactinoma.

Additionally, thyroid symptoms should be checked for, e.g. fatigue, weight changes, skin changes, hair changes, palpitations and/or tachycardia (rapid heartbeat). In patients with hirsutism (unwanted hair growth) and acne, PCOS should be considered.

The patient should also be asked about stressors and exercise routines, as excessive stress or exercise can cause hypogonadotropic hypogonadism. This condition is due to the ovaries producing little or no sex hormones (hypogonadism) as a result of a problem with the pituitary gland or hypothalamus.

As part of the physical examination, the body mass index (BMI) should be calculated, and hirsutism, acne and acanthosis nigricans should be assessed.

Further investigation

Pregnancy is always the first thing that should be suspected when a woman misses her period. — Wikimedia Commons

A urine pregnancy test is usually the first step in evaluating a patient with secondary amenorrhoea. Contraceptives have a failure rate and anyone who is menstruating is potentially fertile. If the pregnancy test is negative, then other signs and symptoms should be considered. For example, hirsutism, acne and menstrual irregularities suggest PCOS.

According to the Rotterdam criteria, a woman may have PCOS if she has at least two of the following:

  • Clinical or chemical hyperandrogenism (too much testosterone in the women’s body, with its accompanying effects),
  • Oligo- or amenorrhoea, or
  • Polycystic ovaries.

PCOS can be diagnosed without further laboratory testing or imaging if a patient has hirsutism and oligo- or amenorrhoea. A thyroid-stimulating hormone (TSH) blood test should be ordered if the history and physical examination do not support PCOS.

Menstrual dysfunction can be caused by both hyperthyroidism and hypothyroidism. If the TSH test is normal, then serum prolactin should be checked. Elevated serum prolactin suggests a prolactinoma. If prolactin levels are normal, then a progestin challenge should be performed. Initially, oral progesterone is given for 10 days.

It is expected that the patient will experience a withdrawal bleed after stopping the progesterone pills. If there is no withdrawal bleed, this indicates that either there is insufficient oestrogen in the body to stimulate the growth of the endometrium, the endometrium has been damaged and is unable to grow, or the menstrual blood is not flowing freely.

If a patient suffering from withdrawal bleeds also has hirsutism, then PCOS, ovarian or adrenal tumours, and Cushing syndrome should all be considered. Otherwise, an oestrogen-progestin challenge should be performed. In this test, the patient is administered both oestrogen and progesterone via a combined oral contraceptive.

Endometrium growth should be triggered by the oestrogen and stopping the contraceptive should result in a withdrawal bleed if the outflow is not blocked. A positive oestrogen-progestin challenge, combined with a negative progestin challenge, is indicative of hypogonadism.

The presence of elevated follicle- stimulating hormone (FSH) and low oestradiol indicates ovarian failure. This is where, despite stimulation by the pituitary, the ovaries do not produce oestrogen.

If both FSH and oestradiol are low, consider functional hypothalamic amenorrhoea or hypothalamic-pituitary dysfunction, which might be due to stress or exercise, or the presence of a pituitary infarct (Sheehan’s syndrome) .

If the oestrogen-progesterone challenge is negative, consider endometrial damage (Asherman’s syndrome) or outflow obstruction (cervical stenosis). It is possible to perform a transvaginal ultrasound in order to check for the presence of haematometra (trapped menstrual blood within the uterus).

The next step in the evaluation of Asherman syndrome would be a hysteroscopy. Part of this procedure is to dilate the cervix in order to allow the hysteroscope – a long, thin tube with a telescope – to enter the uterus. If trapped blood is evacuated during the cervical dilation, this suggests that cervical stenosis might be the cause.


Pregnancy is always the first thing that should be suspected when a woman misses her period. — Wikimedia Commons

Amenorrhoea can be treated depending on its cause. Ovarian failure may be treated with hormone replacement therapy, depending on the patient’s age, symptoms and other risk factors.

Asherman syndrome is treated with hysteroscopic lysis of adhesions, i.e. the non-invasive cutting of the adhesions or scar tissue within the uterus using a hysteroscope. Hypothyroidism is treated with thyroxine replacement therapy.

Hyperthyroidism is treated with thioamides, ablation or surgery. Hyperprolactinaemia is treated with bromocriptine, cabergoline or excision of the prolactinoma. Cervical stenosis is treated with cervical dilation.

The treatment for PCOS includes weight loss, metformin to control insulin resistance, combined oral contraceptives, or endometrial protection with progestin-containing birth control (e.g. medroxyprogesterone acetate depot injection, an etonogestrel subcutaneous implant or a levonorgestrel-releasing intrauterine system).

As pregnancy is the most common cause of amenorrhoea, girls should be taught to monitor their cycles and to use contraception properly to avoid unwanted pregnancies.

Moreover, as amenorrhoea can also be caused by endocrinological disorders, it is essential for doctors to take a female patient’s gynaecological history on regular visits (e.g. date of last period and past pregnancies, if any). If irregularities in menstruation occur, women should contact their healthcare provider for advice.

A patient must be off hormonal contraceptives for at least three months before testing for FSH and oestradiol as hormonal contraceptives can inhibit the hypothalamic-pituitary axis and affect the results. It should also be noted that standard oestradiol tests do not detect ethinyl oestradiol – a birth control oestrogen.

In women on hormonal contraception, amenorrhoea is not uncommon and is not caused by disease. In such a condition, the amenorrhoea requires no further evaluation unless there are other concerns.

By Datuk Dr Nor Ashikin Mokhtar
Published in Star Newspaper, 19 Sep 2022

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