Secondary Amenorrhoea Station

Presenting Complaint - Secondary Amenorrhoea

History of Presenting Complaint:

• Gynaecological History:
  • Her last menstrual period was 7 months ago
  • She had her first period when she was 13 years old
  • Her periods have always been irregular
  • Menses usually last 5 days
  • Cycle length varies from 23 days to 35 days
  • She denies having any heavy menstrual bleeding, dysmenorrhoea, intermenstrual bleeding, or post-coital bleeding
  • She denies having any vulval skin changes and itching, abnormal vaginal discharge, or dyspareunia
• Obstetrics History:
  • She has never been pregnant
  • She has never had any miscarriages or terminations in the past
• Sexual History (very important to rule out pregnancy!):
  • She is sexually active and has 1 partner only (her husband)
  • She is not currently on any contraception and has been trying to get pregnant for the past 5 months. She has sexual intercourse 3-4 times a week.
  • She previously used the copper coil for 7 years and had it removed 6 months ago.
• She admits to having acne and increased hair growth all over her body for the past 5 months (PCOS)
• She denies any history of significant weight loss or extreme exercise regimens (hypothalamic functional amenorrhoea)
• She denies the following symptoms:
  • Hot flushes, night sweats, low libido, vaginal dryness, mood changes (Primary Ovarian Insufficiency (POI))
  • Headaches and vision changes (pituitary gland tumour)
  • Galactorrhoea (hyperprolactinaemia)
  • Heat/cold intolerance, changes to weight, changes to bowel habits, hair or skin changes, sweating, palpitations, anxiety (thyroid dysfunction)
  • Systemic symptoms e.g. unintentional weight loss, fatigue, changes to appetite, night sweats

Previous Medical History

• Otherwise healthy with no significant past medical history

• No recent illnesses or surgery

Drug History

• Nil regular

Allergies

• NKDA

Family History

• No menstrual, gynaecological, or pubertal problems in the family

Social History

• She works as a personal assistant for a law firm

• Lives with her husband

• Drinks alcohol occasionally on weekends. Has never smoked or taken recreational drugs

ICE

• Ideas: “Is there something wrong with my periods and will this affect my fertility?”

• Concerns: “My husband and I want to start a family, and I’m worried that we won’t be able to because of me”

• Expectations: To find out why I haven’t had my periods for the last 7 months

Examination Findings:

• BMI is 27.3 (being overweight or obese is a common finding in women with PCOS)
• General Physical Examination:
  • Hirsutism
  • Acne on face and back
  • Acanthosis nigricans in the axilla (thickened, roughened skin that occurs with insulin resistance)

Most Likely Differentials:

• POI (due to symptoms associated with hypoestrogenism e.g. lack of breast development, hot flushes, night sweats)
• PCOS
• Turner’s Syndrome

Management

• Bedside:
  • Pregnancy Test (the first thing you need to do is to rule out the possibility of pregnancy, even if the patient denies it, as it’s not a diagnosis you would want to miss!)
• Lab:
  • FBC, U&Es, LFTs, CRP for baseline
  • Hormonal Assay (prolactin, TFTs, LH, FSH, oestrogen, testosterone)
• Imaging:
  • Pelvic Ultrasound
    • To check for polycystic-appearing ovaries (“string of pears sign”) + a thickened endometrium (due to oestrogen exposure without post-ovulatory progesterone) – suggestive of PCOS
    • Thin endometrium (due to lack of oestrogen exposure) – suggestive of POI
    • Solid ovarian mass – could indicate hormone-secreting ovarian tumour
  • MRI of the brain (if abnormal neurological findings or elevated prolactin levels to rule out possibility of masses or tumours within the pituitary gland or hypothalamus, or any infiltrative diseases)

1. What is primary amenorrhoea?

• Absence of menses for 3 months in a woman with previously regular menstrual cycles
• Absence of menses for 6 months in a woman with previously irregular menstrual cycles
• Absence of menses for 3 cycle lengths (for women with longer cycle lengths)

2. What is required for normal menstruation to occur?

In order for normal menstruation to occur, 2 things must be present and functioning:

• • Hormones of the HPO (hypothalamic-pituitary-ovarian) axis
  • All relevant anatomy

The hypothalamus releases GnRH (gonadotropin releasing hormone) -> stimulates anterior pituitary gland to release the gonadotropins FSH and LH -> stimulates ovaries to release the female sex hormones oestrogen and progesterone -> endometrial proliferation and stabilisation -> menses

3. What are the causes of secondary amenorrhoea?

Secondary amenorrhoea can be caused by multiple factors that affect the HPO axis. A useful way to understand the different causes of secondary amenorrhoea is to think about which part of the HPO axis is affected:

• Hypothalamic Dysfunction:
  • Functional hypothalamic amenorrhoea
  • Significant chronic conditions/systemic illnesses e.g. Type 1 diabetes, coeliac disease, IBD, cystic fibrosis etc.
  • Injury e.g. by radiotherapy, traumatic brain injury
  • Infiltrative diseases e.g. sarcoidosis, hemochromatosis
• Pituitary Gland Dysfunction:
  • Sheehan syndrome
  • Hyperprolactinaemia secondary to:
    • Prolactinomas (headache, vision problems) – most common
    • Medications e.g. antipsychotics, tricyclic antidepressants, metoclopramide
    • Hypothyroidism (↑TRH -> ↑Prolactin)
  • Infection e.g. encephalitis, meningitis (resulting in damage to the pituitary gland)
  • Pituitary gland tumour e.g. pituitary adenoma, craniopharyngioma
• Ovarian Dysfunction:
  • POI (primary ovarian insufficiency)/POF (premature ovarian failure)
  • PCOS
  • Menopause
• Uterine/Vaginal Aetiologies:
  • Asherman’s Syndrome
  • Cervical Stenosis
  • Female Genital Mutilation
• Other (Hormonal Aetiologies):
  • Thyroid Dysfunction – Hypothyroidism or hyperthyroidism
  • Congenital adrenal hyperplasia
  • Cushing’s syndrome
  • Adrenal insufficiency
  • Androgen-secreting tumours (ovarian or adrenal)
  • Oestrogen-secreting tumours (ovarian)

NB – Pregnancy is the most common cause of secondary amenorrhoea and should always be ruled out first!

4. What is polycystic ovarian syndrome (PCOS)?

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 10-15% of women in this age group. It is characterised by:

• Elevated LH:FSH ratio (i.e. ↑LH & ↓FSH)
• Hyperandrogenism (due to ↑LH & hyperinsulinaemia usually seen with PCOS)
• Chronic anovulation (↓FSH contributes to poor egg development and inability to ovulate, resulting in oligomenorrhoea/amenorrhoea)
• Ovarian cysts
• Metabolic syndrome (e.g. obesity, insulin resistance, dyslipidaemia, HTN)

Aetiology

The exact cause of PCOS is unknown, but genetics and environmental factors likely play a role.

Clinical Presentation

• Oligomenorrhoea or amenorrhoea (due to ↓FSH)
• Hirsutism (due to hyperandrogenism)
• Acne (due to hyperandrogenism)
• Male-pattern baldness (due to hyperandrogenism)
• Infertility (due to irregular ovulation or anovulation)

Associated Conditions

• Metabolic Disturbances (e.g. obesity, insulin resistance, T2DM, cardiovascular disease, HTN, hypercholesterolaemia)
• Endometrial hyperplasia and cancer

Diagnosis

The Rotterdam criteria is commonly used to make the diagnosis, and involves a combination of clinical evaluation, physical examination, laboratory tests, and imaging.

Diagnosis requires 2 of the following 3 criteria:

• Hyperandrogenism (clinical e.g. hirsutism, acne, male-pattern baldness OR biochemical e.g. ↑testosterone)
• Olig- or anovulation (evidenced by oligo- or amenorrhoea)
• Polycystic ovaries on US (>12 antral follicles in one ovary and/or ovarian volume >10cm³
  • NB – despite the name “polycystic”, patients don’t require having ovarian cysts for a diagnosis of PCOS
  • Also note that pelvic US is not reliable in adolescents for the diagnosis of PCOS

Management

Management of PCOS aims to address symptoms and reduce the risk of long-term complications:

• Lifestyle advice on diet and exercise to promote weight loss can improve insulin sensitivity and hormone levels.
• Hirsutism:
  • Weight loss may improve symptoms
  • Mechanical hair removal (e.g., waxing, laser hair removal)
  • Medications:
    • 1^st line: Co-cyprindiol (Dianette) is a COCP licensed for the treatment of hirsutism and acne. It has an anti-androgenic effect, works as a contraceptive, and regulates periods. However, the downside is a significantly increased risk of VTE. For this reason, co-cyprindiol is usually stopped after 3 months of use.
    • Antiandrogens e.g. spironolactone, finasteride, cryproterone, flutamide
  • Acne:
    • 1^st line: Co-cyprindiol (Dianette)
    • Other standard treatments for acne e.g. topical adapalene, benzyl peroxide, topical antibiotics e.g. clindamycin, oral tetracycline antibiotics, Roaccutane etc.
  • Infertility:
    • 1^st line: weight loss (can restore regular ovulation). If this fails, other options can be tried below.
    • Clomiphene citrate (selective oestrogen receptor modulator). It works by reducing oestrogen levels, leading to increased FSH)
    • Metformin and Letrozole (letrozole is an aromatase inhibitor and reduces oestrogen levels, leading to increased FSH)
    • Laparoscopic ovarian drilling
    • Associated reproduction techniques e.g. IVF
  • Endometrial protection (due to increased risk of endometrial hyperplasia and cancer):
    • A pelvic US first needs to be done to assess the endometrial thickness. If the endometrial thickness >10mm, the need to be referred for a biopsy to exclude endometrial hyperplasia or cancer
    • Mirena coil for continuous endometrial protection
    • Inducing a withdrawal bleed at least every 3-4 months with either cyclical progestogens or COCP
  • Regular screening and treatment for metabolic diseasesg. T2DM, dyslipidaemia, HTN, cardiovascular disease etc.
  • Psychological Support - PCOS can have significant emotional and psychosocial impacts. Offering psychological support, counselling, and access to support groups can help individuals cope with the emotional challenges of PCOS.

5. What are the expected hormone levels in someone with PCOS?

• Increased:
  • LH
  • Androgens e.g. testosterone
  • Oestrogen (adipocytes produce oestrogen -> inhibits FSH)
  • Insulin (due to increased insulin resistance)
• Decreased:
  • FSH (due to increased inhibition by oestrogen)
  • Progesterone (due to anovulation)
  • Sex-hormone binding globulin (SHBG) – due to increased insulin suppressing SHBG production by the liver

6. Why are women with PCOS at an increased risk of endometrial hyperplasia and cancer?

Under normal circumstances, the corpus luteum releases progesterone after ovulation. Women with PCOS do not ovulate or ovulate infrequently, resulting in irregular menstrual cycles or amenorrhoea. The lack of ovulation leads to unopposed oestrogen production, which stimulates endometrial growth. Without regular endometrial shedding that occurs during menstruation, the endometrial lining can become thicker (hyperplasia) over time, a precursor to developing endometrial cancer. This is similar to giving unopposed oestrogen in women on hormone replacement therapy.

7. In patients whose clinical examination and lab investigations are unremarkable, how would you evaluate their secondary amenorrhoea?

You would need to do a progestin challenge, which involves assessing for withdrawal bleeding following a course of oral progesterone or an IM injection of progesterone. Patients who do not bleed after being challenged with progestin must be challenged with oestrogen and progestin.