Oligomenorrhoea

Definition: Infrequent menstrual bleeding defined as < 9 spontaneous menstrual cycles per year (cycle length > 35 days).
Key consideration: Always exclude pregnancy first.

Differential Diagnosis (organised by mechanism)

Category	Examples	Key Clues
Physiological / Life-stage	Pregnancy Perimenopause Lactation	Positive β-hCG, elevated FSH/LH ratio in menopause
Hypothalamic–Pituitary	Hyperprolactinaemia Functional hypothalamic amenorrhoea (stress, excessive exercise, weight loss), Pituitary adenoma	Low/normal LH & FSH, ↑ prolactin, MRI pituitary if tumour suspected
Thyroid & Adrenal	Hypothyroidism Cushing syndrome Late-onset CAH (21-hydroxylase deficiency)	TFTs, dexamethasone suppression test, 17-OHP levels
Ovarian / Androgen Excess	Polycystic ovary syndrome (PCOS) Androgen-secreting tumours (ovarian, adrenal) Exogenous androgens	Clinical/biochemical hyperandrogenism, markedly ↑ testosterone or DHEA-S with tumours
Iatrogenic	Combined oral contraceptive “pill withdrawal” Progesterone-only contraception GnRH analogues Antipsychotics (via ↑ prolactin)	Medication history
Uterine / Outflow Tract	Asherman syndrome (intra-uterine adhesions post-curettage myomectomy, infection)	Normal hormonal profile; hysteroscopy or HSG shows adhesions
Metabolic / Weight-related	Obesity (via insulin resistance → ↑ ovarian androgens)	BMI, features of metabolic syndrome

Polycystic ovary syndrome

Pathophysiology

Central feature: insulin resistance → compensatory hyperinsulinaemia which stimulates theca cells to overproduce ovarian androgens.
Multifactorial aetiology; genetic and environmental factors interplay.

Epidemiology

Measure	Data
Polycystic ovarian morphology on ultrasound	~33 % of reproductive-age females; majority are asymptomatic
PCOS (NIH/Rotterdam criteria)	8–13 % prevalence in Australian women

Clinical Spectrum

Reproductive Manifestations
- Chronic anovulation → oligomenorrhoea or secondary amenorrhoea
- Infertility due to anovulation
- Dysfunctional uterine bleeding (DUB)
- ↑ risk endometrial hyperplasia / carcinoma (unopposed oestrogen)
Androgen Excess Features
- Hirsutism (Ferriman–Gallwey > 8)
- Moderate–severe acne
- Androgenic alopecia (less common)
- Polycystic ovarian morphology on transvaginal ultrasound (≥ 20 follicles < 10 mm or ovarian volume > 10 mL)
Metabolic Morbidities
- Insulin resistance & compensatory hyperinsulinaemia
- Dyslipidaemia (↑ LDL-C, ↑ TG, ↓ HDL-C)
- Impaired glucose tolerance, gestational diabetes, type 2 diabetes
- Hypertension
- Obesity (60–80 % of Australian cases)
- Cardiovascular disease: strongly associated risk factors, but prospective data have not yet shown a consistent increase in myocardial infarction or stroke events.

Diagnosis (Rotterdam consensus group criteria)

PCOS is diagnosed when ≥ 2 of 3 features are present after excluding other causes of hyperandrogenism or anovulation:

Criterion	Details
Oligo- / Anovulation	< 9 spontaneous menses / year or cycle length > 35 d
Hyperandrogenism	• Clinical: hirsutism, moderate–severe acne, androgenic alopecia • Biochemical: ↑ total or free testosterone, ↑ free androgen index (FAI), or ↑ DHEA-S
Polycystic ovarian morphology (PCOM)	On high-resolution trans-vaginal US: ≥ 20 follicles (2–9 mm) in either ovary or ovarian volume > 10 mL (≥ 12 follicles acceptable if older scanner)

Exclude: late-onset CAH (17-OHP), hyperprolactinaemia, androgen-secreting tumours, Cushing syndrome, thyroid disease, pregnancy.

Assessment

Domain	Key Points
History	• Menstrual pattern (oligo/amenorrhoea, breakthrough bleeding, infertility) • Clinical androgen excess (hirsutism, acne, alopecia; virilisation suggests tumour) • Metabolic features: obesity, GDM, T2DM, metabolic syndrome, NAFLD, OSA • Psychosocial: depression, anxiety, eating disorder, body-image / sexual concerns • Family history: PCOS, T2DM, obesity, premature CAD
Examination	• BMI, waist, BP • Ferriman-Gallwey hirsutism score • Acne grade, scalp thinning • Acanthosis nigricans (insulin resistance) • Thyroid palpation; visual fields if galactorrhoea ± ↑PRL

Investigations

eneral Principles

Perform hormonal testing ideally on day 2–5 of a spontaneous or induced cycle.
If amenorrhoeic, perform hormonal tests on a random day after excluding pregnancy.
Diagnosis is based on Rotterdam criteria (≥2 of 3) after exclusion of other causes.

1. Hormonal and Endocrine Investigations

Test	Purpose	Interpretation
β-hCG	Exclude pregnancy	Always check if amenorrhoea
FSH, LH, Estradiol	Assess gonadotropin axis	LH:FSH >2:1 classic in PCOS (50%) but not diagnostic. Rule out hypogonadotropic hypogonadism or premature ovarian failure.
TSH	Exclude hypothyroidism	Hypothyroidism may cause anovulation
Prolactin	Rule out hyperprolactinaemia	Mild elevation common in PCOS. >2× ULN or symptoms → consider pituitary MRI
Total Testosterone SHBG → Free Androgen Index (FAI)	Assess biochemical hyperandrogenism	Free testosterone is more sensitive. Hormonal contraception suppresses levels—test ≥3 months post-cessation with alternative contraception.
DHEA-S	Assess adrenal androgen excess	DHEA-S >700 μg/dL suggests adrenal tumour. Normal: ~250–300 μg/dL
17-Hydroxyprogesterone (17-OHP)	Exclude non-classical CAH	Test in follicular phase. Elevation suggests 21-hydroxylase deficiency (late-onset CAH)

2. Pelvic Ultrasound (TVUS Preferred)

Feature	Purpose
Ovarian morphology	Diagnostic if ≥20 follicles (2–9 mm) in either ovary OR ovarian volume >10 mL (Rotterdam)
Endometrial thickness	Assess for unopposed oestrogen → hyperplasia; biopsy if thickened or prolonged amenorrhoea

Important notes:

Ultrasound is not reliable for PCOM diagnosis in adolescents.
Up to 70% of healthy teens have PCOM; thus, do not use ultrasound for diagnosis <8 years post-menarche (per Radiopaedia & international PCOS guideline).
In adolescents, diagnosis should rely on persistent hyperandrogenism and menstrual irregularity ≥2 years post-menarche.

3. Metabolic Assessment

Test	Purpose
75 g OGTT (preferred over fasting glucose)	Detect impaired glucose tolerance or diabetes
Insulin (optional)	Assess insulin resistance
Fasting Lipids	Assess cardiovascular risk
ALT ± liver ultrasound	Screen for NAFLD

4. Conditional / Second-Line Testing

Test	Indication
Dexamethasone Suppression Test (1 mg overnight)	Suspect Cushing syndrome (e.g., centripetal obesity, striae, proximal weakness)
MRI Pituitary	If prolactin persistently >2× ULN or galactorrhoea
CT Adrenals or Tumour Work-up	If testosterone >5 nmol/L, DHEA-S >700 μg/dL, or signs of virilisation (deep voice, clitoromegaly, rapid onset hirsutism)

what if patient already on combined hormonal contraceptives ?

Usually — a ≥ 3-month wash-out is recommended when you want a definitive diagnostic assessment. Hormonal contraception (especially combined oral contraceptive pills, COCPs) suppresses the hypothalamic-pituitary-ovarian axis, increases sex-hormone-binding globulin (SHBG) and alters follicular dynamics; this can mask the biochemical and ultrasound hallmarks of PCOS. Australian and international guidelines advise ceasing the pill (and offering non-hormonal cover) for about three cycles before measuring androgens or performing a diagnostic pelvic ultrasound. racgp.org.au mja.com.au

Impact of OCPs on individual investigations

Investigation	Expected effect while on COCP	Diagnostic implication	Preferred approach
LH, FSH, Estradiol	↓ LH & FSH (and thus LH:FSH ratio)	May obscure the “classic” LH:FSH > 2 : 1 pattern	Test ≥ 3 m off COCP if assessing anovulation/pituitary axis
Total Testosterone	↓ Ovarian androgen output → total T falls	Masks hyperandrogenism	Stop pill; draw in early follicular phase
SHBG & Free Androgen Index (FAI)	SHBG ↑ 2- to 3-fold → free T & FAI fall	Strongly blunts biochemical hyperandrogenism	Assess ≥ 3 m off pill
DHEA-S	Mostly adrenal source → minimal change	Still interpretable	Can test on pill if needed
17-Hydroxy-progesterone	Mildly reduced	May hide NCCAH; test off pill if ruling out CAH
Prolactin	Usually normal; mild rise possible	Meaningful elevation (> 2× ULN) still significant	No need to delay unless borderline
Pelvic ultrasound (ovarian morphology)	Follicle development suppressed → ↓ antral follicle count; ovarian volume shrinks	Under-diagnoses polycystic ovarian morphology (PCOM)	Scan ≥ 3 m off pill (transvaginal if sexually active)
Metabolic tests (OGTT, fasting lipids)	Little or no effect	Results valid	Can test on pill

Class	Typical HPO-axis effect	Key hormonal changes	Implications for PCOS tests
Traditional progestin-only pill (POP)(levonorgestrel 30 µg “mini-pill”)	Minimal ovulation suppression (ovulates in ≥40 % cycles)	Slight ↑ SHBG, mild ↓ free T	Small blunting of biochemical hyper-androgenism; LH/FSH ratio usually preserved; ovarian morphology largely unchanged
Desogestrel 75 µg POP (“new POP”)	>95 % ovulation inhibition	↑ SHBG, ↓ LH & FSH, ↓ free T	Can mask hyper-androgenism and anovulation; follicular arrest → reduced AFC
Etonogestrel implant (Nexplanon / Implanon-NXT)	Consistent ovulation suppression	↓ E2 and androgens; ↑ SHBG	Biochemistry and ultrasound unreliable until after removal (axis recovery within ~4–8 wk)
Depot medroxyprogesterone acetate (DMPA)	Robust pituitary shut-down for ≥14 wk per injection	Marked ↓ LH, FSH, E2 and androgens	Strongly masks all three diagnostic domains; HPO recovery takes 4–9 mo after last dose cognixpulse.com
Levonorgestrel intra-uterine system (LNG-IUS, Mirena/Kyleena)	Largely local effect; ovulation in ≥75 % cycles	Minor systemic LNG, slight ↑ SHBG; androgen profile unchanged	Minimal interference; labs and ultrasound are usually interpretable without removal ajog.org sciencedirect.com

Recommended wash-out periods for a diagnostic PCOS work-up

Method	Suggested interval off contraception*	Rationale
Traditional POP	≥1 menstrual cycle (at least 4 wk)	Limited axis suppression; SHBG normalises quickly
Desogestrel POP	≥3 mo	Comparable suppression to a low-dose COCP
Etonogestrel implant	Remove and wait ≥6 wk before testing	Serum etonogestrel undetectable and ovulation returns in ~1 mo; SHBG falls over 4–8 wk
DMPA injection	Schedule investigations ≥6 mo after last 150 mg IM/SC dose	Median time to ovulation recovery 28 wk; LH/FSH remain low for months
LNG-IUS	No mandatory wash-out	Diagnostic accuracy acceptable while in situ

*Intervals are drawn from the 2023 International PCOS Guideline, FSRH injectable guidance, and pharmacokinetic data; err on the longer side if cycles are still anovulatory.

Practical approach

Clarify your diagnostic goal
Full Rotterdam criteria confirmation requires that hyper-androgenism, ovulatory status and ovarian morphology reflect the woman’s native physiology.
Plan contraception in the interim
- Non-hormonal options: copper IUD, condoms/diaphragm.
- If hormonal contraception must continue (e.g. LNG-IUS for menorrhagia), document the limitation and base diagnosis on the other two criteria (e.g. irregular cycles + clinical hyper-androgenism).
Time your sampling
Draw androgens, LH, FSH, 17-OHP, TSH and prolactin early morning, day 2–5 when cycles have returned.
Ultrasound timing
Perform a trans-vaginal scan ≥3 mo after ceasing systemic progestins (implant/POP) or ≥6 mo post-DMPA to avoid under-counting follicles.
Communicate expectations
Explain the reason for the “drug holiday” and arrange follow-up to interpret results; offer bridging copper IUD or condoms as needed. Hormones Australia recommend the same three-month window off hormonal contraception for accurate androgen tests. hormones-australia.org.au
Short-acting POPs may need only one cycle wash-out; long-acting progestin-only methods (implant, DMPA) need ≥6 wk to many months for the HPO axis to recover.
The LNG-IUS seldom confounds testing and can usually stay in place.

Management:

1. Lifestyle & Weight Management (first-line)

Counselling – explain reproductive, metabolic and psychological aspects; set realistic goals.
Weight reduction (BMI > 25 kg/m²) – even 5 % loss improves cycle regularity, restores ovulation, lowers depression scores and roughly halves future type 2 diabetes risk in high-risk women.
Dietary strategy – calorie deficit with nutrient-dense, low-GI or Mediterranean pattern; refer to dietitian where possible.
Physical activity – minimum 150 min/wk moderate aerobic (or 75 min vigorous) + two resistance sessions; aim for 300 min/wk if further weight loss needed.
Behaviour-change support – motivational interviewing, structured programs, digital tools.

2. Endometrial protection & cycle control

Intervention	Typical regimen	Key points
Low-dose COCP (≤20 µg EE)	Continuous	Regulates menses, treats acne/hirsutism; lower oestrogen dose minimises adverse effects on insulin resistance & lipids
Cyclic progestin	Medroxyprogesterone acetate 10 mg daily for 10 days every 2–3 mo	Induces withdrawal bleed; prevents endometrial hyperplasia in oligo-/amenorrhoea
Metformin	500 mg daily → up-titrate to 1.5–2 g/day	↓ hepatic gluconeogenesis →↓ fasting insulin → less thecal‐cell drive to produce androgens ↑ insulin-mediated glucose uptake (Improves whole-body insulin sensitivity) Improves menstrual cyclicity and ovulation; consider if COCP contraindicated or insulin resistance prominent

3. Ovulation induction & fertility care

Pre-conception optimisation – smoking cessation, folic acid ≥400 µg/day, healthy weight, exercise; counsel on age-related fertility decline.
First-line ovulation induction
- Letrozole 2.5–7.5 mg days 2–6 (preferred, not TGA-approved but guideline-endorsed).
- Clomiphene citrate 50–150 mg days 2–6 – pregnancy in ≈40–45 % within 6 cycles.
- Metformin (± clomiphene) – similar efficacy to clomiphene alone in lean women (BMI < 30–32 kg/m²); beneficial in CC-resistant or insulin-resistant cases.
Second-line
- FSH / HMG low-dose step-up protocols under specialist monitoring.
- Laparoscopic ovarian drilling (LOD) when CC ± metformin fails and no other infertility factors.
Third-line – IVF/ICSI if anovulation persists or other factors coexist.

4. Hirsutism / androgen-related symptoms

Step	Measure	Notes
1. Lifestyle	≥5 % weight loss	Reduces free testosterone; may modestly improve hair growth
2. Cosmetic	Shaving, waxing, depilatory creams; laser/electrolysis for long-term	Offer early to improve QoL
3. Pharmacologic	• Low-dose COCP (first-line) • After ≥6–12 m, add anti-androgen if needed: – Spironolactone 50–100 mg bd – Cyproterone acetate 25 mg days 1–10 of COCP cycle	Reliable contraception essential – anti-androgens are teratogenic.
4. Adjuncts	Metformin (modest effect); topical eflornithine for facial areas	10-25 % reduction in total and free testosterone

5. Cardiometabolic risk reduction

Screen – BP yearly; OGTT or HbA1c q 1–3 y; fasting lipids q 2–4 y.
Lifestyle intervention (≥7 % weight loss + 150 min activity) cut incident diabetes by ≈58 % in high-risk cohorts.
Metformin 1.5–2 g/day reduces diabetes risk ≈31 % when lifestyle change is insufficient or BMI ≥ 35 kg/m².
Address hypertension, dyslipidaemia, sleep apnoea, and mental health proactively.

Key take-aways

Weight-centred lifestyle therapy is foundational and often sufficient to restore cycles and reduce long-term metabolic risk.
Low-dose COCP or cyclical progestin protects the endometrium; add metformin if cycles remain irregular or insulin resistance dominates.
Escalate to ovulation induction, LOD or IVF in a stepwise fashion for infertility; provide early fertility counselling.
Combine cosmetic, hormonal and anti-androgen therapy for hirsutism, always with reliable contraception.
Long-term cardiometabolic surveillance (and timely treatment of risk factors) is essential across the lifespan.

Indications for specialist consultation

Abnormal unexplained per vaginal bleeding or very heavy bleeding
Anovulatory dysfunctional uterine bleeding not responding to pharmacological treatment
Infertility management, especially if there are other infertility factors involved such as a poor semen analysis
High suspicion of other hyperandrogenic disorders needing exclusion or advice on the exclusion of such disorders
Diagnosis of T2DM
Severe hypercholesterolaemia
Recurrent miscarriage
Patient not tolerant of usual treatments
Treatment failures
Follow up
- diabetes screening every 1-3 years
- Monitor MH concerns
- Cycle regularion
- Discuss family planning
- Assessment cardiovascular disease/ BP/lipids
- Hirsutism management
- Weight loss 5-10%
- Regular exercise
- Monitor sleep apnoea

Hirsutism

Excessive terminal hair growth in androgen-dependent skin areas which is socially unacceptable to the patient
Affects 5-15% of women

Causes of Hirsutism

Androgen-Dependent Causes:
- Androgen Excess Disorders:
  - Ovary:
    - Polycystic Ovary Syndrome (PCOS)
    - Ovarian Tumour
  - Adrenal Gland:
    - Late-Onset Congenital Adrenal Hyperplasia (LOCAH)
    - Cushing’s Syndrome
    - Adrenal Tumour
- Hyperprolactinemia (HyperPrl)
- Drug-Induced:
  - Use of androgens can increase androgen levels and lead to hirsutism.
- Idiopathic Hirsutism:
  - No identifiable underlying cause.
- Increased Peripheral Sensitivity to Androgens:
  - Increased sensitivity of hair follicles to androgens.
Androgen-Independent Causes (Hypertrichosis):
- Familial Hypertrichosis:
  - Genetic predisposition to increased body hair.
- Medication-Induced Hypertrichosis:
  - Common medications include:
    - Cyclosporine
    - Diazoxide
    - Minoxidil

Investigation for Hirsutism

Pelvic Ultrasound:
- To evaluate ovarian abnormalities such as cysts or tumours.
Hormonal Assessment:
- Timing: Conduct tests on Day 2-5 of the menstrual cycle for those with regular cycles or oligomenorrhea.
- Tests to Include:
  - Beta-hCG (BHCG): To rule out pregnancy, especially in cases of amenorrhea.
  - FSH (Follicle-Stimulating Hormone) and LH (Luteinizing Hormone).
  - Estradiol (E2).
  - Thyroid Function Tests (TFT).
  - Prolactin (Prl).
  - Androgens:
    - 17-Hydroxyprogesterone (17-OHP).
    - Dehydroepiandrosterone Sulfate (DHEAS).
    - Testosterone (T).
    - Sex Hormone-Binding Globulin (SHBG).
    - Free Androgen Index (FAI).

Hyperandrogenism

Definition:
- Hyperandrogenism refers to excessive levels of circulating male sex hormones (e.g., testosterone) in females, leading to various effects on the body.

Causes of Hyperandrogenism:

Ovarian Disorders:
- Polycystic Ovary Syndrome (PCOS)
- Ovarian Tumours:
  - Benign (non-cancerous)
  - Malignant (cancerous)
Adrenal Gland Disorders:
- Congenital Adrenal Hyperplasia:
  - Partial deficiency of the enzyme 21-hydroxylase (late-onset CYP21A2 deficiency).
- Adrenal Tumours:
  - Benign or malignant adrenal tumours.
Pituitary Gland Disorders:
- Cushing Syndrome:
  - Due to excessive production of adrenocorticotrophic hormone (ACTH).
- Acromegaly:
  - Excessive growth hormone and insulin-like growth factor (IGF-1) production.
- Prolactinoma:
  - Tumour that produces prolactin, which stimulates the adrenal gland.
Obesity and Metabolic Syndrome:
- Increased androgen production in the adrenal glands and body fat in response to insulin and IGF-1.
- Reduced vitamin-D production in the skin.
Medications:
- Anabolic steroids
- Recombinant human IGF-1

Mechanisms of Hyperandrogenism:

High Overall Levels of Circulating Testosterone.
Increased Free Testosterone:
- Due to low levels of sex-hormone-binding-globulin (SHBG), which normally binds testosterone tightly.
Conversion of Weak Androgens to Stronger Androgens:
- Conversion of weaker androgens to dihydroxytestosterone (DHT) by Type 1 5-alpha-reductase in the sebaceous gland.
Adrenal Steroid Conversion:
- Adrenal steroids convert first to androstenedione by 3-beta-hydroxysteroid dehydrogenase, and then to testosterone by 17-beta hydroxysteroid dehydrogenase.
Increased Skin Sensitivity to DHT.
Effects of Insulin and IGF-1.

Effects of Hyperandrogenism:

Seborrhoea (oily skin)
Acne
Hidradenitis Suppurativa
Hirsutism (excess body/facial hair)
Female Pattern Balding (alopecia)
Male Pattern Balding in Females
Irregular Menstruation
Masculine Physical Changes:
- Increased muscle mass, decreased breast size.
- Deepening of the Voice with prominent larynx (voice box).
- Clitoral Enlargement with increased libido (virilisation).
Infertility
Associated Type 2 Diabetes due to insulin resistance.
Obesity

Signs of Hyperandrogenism:

Baseline Laboratory Investigations:

Follicle Stimulating Hormone (FSH)
Luteinising Hormone (LH)
Oestradiol
Prolactin
Testosterone
Sex Hormone Binding Globulin (SHBG)
17-Hydroxyprogesterone
Dehydroepiandrosterone Sulfate (DHEAS)
Thyroid Function Tests
Pelvic Ultrasound Scan:
- To evaluate for ovarian cysts.

	Mildly decreased	Mildly increased	Significantly increased
Serum Prolactin	Functional Hypothalamic Amenorrhea	Polycystic Ovary Syndrome (PCOS)	Pituitary Adenoma Hypothyroidism
LH) FSH	Functional Hypothalamic Amenorrhea Constitutional delay of Puberty Congenital Adrenal Hyperplasia (CAH)	Normal Outflow tract obstruction Non-endocrine causes of Amenorrhea Polycystic Ovary Syndrome (PCOS) – may also be low normal	Primary Ovarian Insufficiency Menopause Turner Syndrome
Serum Testosterone	Functional Hypothalamic Amenorrhea Menopause Primary Ovarian Insufficiency	Polycystic Ovary Syndrome (PCOS)	Congenital Adrenal Hyperplasia Adrenal or ovarian tumor Cushing Syndrome Genetic male Androgen insensitivity syndrome 5a-Reductase Deficiency
17-OHP			Congenital Adrenal Hyperplasia (late onset)
DHEA-S		Congenital Adrenal Hyperplasia Hyperprolactinemia Polycystic Ovary Syndrome (PCOS)
Anti-Mullerian Hormone	Primary Ovarian InsufficiencyMenopause	Polycystic Ovary Syndrome (PCOS)	Functional Hypothalamic Amenorrhea
Estradiol	poor ovarian function low in most Amenorrhea except for outflow obstruction

Polycystic ovarian syndrome (PCOS)