PCOS, hypogonadism, Turner and Klinefelter syndromes, infertility and tests of the HPG axis

Overview

The hypothalamic–pituitary–gonadal (HPG) axis controls puberty, sex hormone production and fertility. Disorders show up as delayed puberty, amenorrhoea, hirsutism, low libido or infertility. Most PGET questions can be solved by pairing the sex steroid level with LH and FSH to place the problem in the gonad or above it, and by knowing the classic syndromes.

The HPG axis

• The hypothalamus releases GnRH in pulses (driven by kisspeptin). Pulsatile GnRH stimulates the pituitary; continuous GnRH (or long-acting analogues) switches it off.
• LH: stimulates Leydig cells to make testosterone (men) and theca cells to make androgens (women), and triggers ovulation (mid-cycle surge).
• FSH: stimulates Sertoli cells and spermatogenesis (men) and granulosa cells, follicle growth and aromatisation of androgens to oestradiol (women).
• Feedback: testosterone and oestradiol suppress LH; inhibin (from Sertoli and granulosa cells) suppresses FSH.
• Prolactin lowers GnRH pulse frequency, so hyperprolactinaemia causes hypogonadism.

Interpreting HPG axis tests

Practical points

• Measure testosterone in the morning (before 11 am), fasting, and repeat if low. Obese men and men with diabetes have low SHBG, so total testosterone may be low while the active hormone is normal.
• Mid-luteal progesterone (about 7 days before the expected period: day 21 of a 28-day cycle, day 25 of a 32-day cycle) confirms ovulation; a level above about 30 nmol/L indicates ovulation.
• In women, FSH and LH are best taken in the early follicular phase (days 2–5); a single high value may simply be the mid-cycle surge, so repeat before diagnosing ovarian failure.
• Anti-Müllerian hormone (AMH) from granulosa cells reflects ovarian reserve and can be taken any day: high in PCOS, low in premature ovarian insufficiency and menopause.
• Dynamic tests (now rarely needed): an hCG test (testosterone rises if Leydig cells are present; no rise suggests anorchia or primary failure), a GnRH (LHRH) test (pituitary reserve; a rise after GnRH priming points to a hypothalamic cause), and a clomifene test (blocks oestrogen feedback; LH and FSH should rise if the hypothalamus works).
• Prolactin and TSH belong in every amenorrhoea or hypogonadism work-up; secondary hypogonadism needs pituitary MRI and other pituitary hormones.
• Primary hypogonadism needs a karyotype.

Polycystic ovary syndrome (PCOS)

The commonest endocrine disorder of young women, the commonest cause of hirsutism, and the commonest cause of anovulatory infertility.

Pathophysiology (just what explains the facts)

• Faster GnRH pulses → more LH → theca cells make more androgens.
• Insulin resistance and high insulin act with LH on theca cells to increase androgen, and lower liver SHBG, so more androgen is active.
• Arrested follicles form many small peripheral cysts; no ovulation → no progesterone → unopposed oestrogen on the endometrium.

Clinical features

• Oligomenorrhoea or amenorrhoea from around menarche; subfertility.
• Hirsutism, acne, male-pattern hair thinning.
• Obesity (central), acanthosis nigricans.
• Some have regular cycles or no hirsutism; features blend with normal.

Rotterdam criteria (any 2 of 3)

1. Clinical or biochemical hyperandrogenism.
2. Oligo-ovulation or anovulation.
3. Polycystic ovaries on ultrasound (many small follicles around a dense, bright stroma, or enlarged ovaries).

And exclusion of other causes: non-classic congenital adrenal hyperplasia (17-OH progesterone), Cushing syndrome, androgen-secreting tumours, hyperprolactinaemia, thyroid disease.

Investigations

• Testosterone normal or mildly raised; SHBG low; androgen index (testosterone ÷ SHBG × 100) high.
• LH raised in many (LH:FSH ratio high, but not always on one sample).
• Prolactin may be mildly raised (usually below about 1500 mU/L).
• Pelvic ultrasound; OGTT or HbA1c and lipids for metabolic risk.
• Red flags for a tumour: rapid onset, virilisation (clitoromegaly, deep voice, frontal balding), testosterone well above the PCOS range.

Long-term risks

• Type 2 diabetes and gestational diabetes (insulin resistance).
• Endometrial hyperplasia and cancer (unopposed oestrogen with infrequent periods).
• Dyslipidaemia, hypertension, cardiovascular risk, fatty liver, obstructive sleep apnoea, depression.

Management

Male hypogonadism

Features

• Before puberty: delayed puberty, small testes and penis, eunuchoid proportions (long arms and legs because epiphyses close late).
• After puberty: low libido, erectile dysfunction, tiredness, loss of body hair and muscle, gynaecomastia, small soft testes, osteoporosis, infertility.

Causes

Treatment

• Testosterone replacement (gel or injections) for symptoms and bone protection when fertility is not wanted. Check haematocrit and prostate in older men.
• For fertility in secondary hypogonadism: hCG (acts like LH) followed by FSH, or pulsatile GnRH if the pituitary is intact.
• Primary testicular failure cannot be stimulated; options are micro-dissection testicular sperm extraction (microTESE) with ICSI, or donor sperm.

Kallmann syndrome

• Isolated GnRH deficiency with anosmia or hyposmia. GnRH neurones fail to migrate with the olfactory neurones from the nasal placode.
• Often X-linked (KAL1/ANOS1); may have cleft palate, renal agenesis, colour blindness.
• Delayed puberty, low LH, FSH and testosterone; normal height (often tall, eunuchoid).
• Normosmic forms exist (e.g. kisspeptin receptor mutations).
• Treat with sex steroids for puberty; gonadotrophins or pulsatile GnRH for fertility.

Klinefelter syndrome (47,XXY)

• The commonest sex chromosome disorder in males (about 1 in 1000 or more); extra X usually from non-disjunction (maternal or paternal meiosis I).
• Primary hypogonadism: seminiferous tubule dysgenesis and Leydig cell loss.
• Features: tall, long legs, small, firm testes, gynaecomastia, sparse body hair, learning or behavioural difficulties; puberty may start normally then stall.
• Labs: low or low-normal testosterone, high FSH and LH, azoospermia. Diagnosis by karyotype.
• Associations: male breast cancer, type 2 diabetes, osteoporosis, autoimmune disease, venous thrombosis, mediastinal germ cell tumours.
• Treatment: testosterone (does not restore fertility); microTESE with ICSI may allow biological children.

Female hypogonadism and amenorrhoea

• Primary amenorrhoea: no periods by 15 years with secondary sexual characteristics, or by 13 without them. Commonest causes include Turner syndrome, constitutional delay, hypogonadotropic hypogonadism, Müllerian agenesis, androgen insensitivity (46,XY, breasts but no pubic hair), imperforate hymen.
• Secondary amenorrhoea: absence of periods for 3–6 months after previously normal cycles. First exclude pregnancy; then think PCOS, hypothalamic amenorrhoea (low weight, stress, exercise), hyperprolactinaemia, thyroid disease, premature ovarian insufficiency, Asherman syndrome (uterine adhesions after curettage or genital TB).

• Treatment is of the cause; if oestrogen deficiency persists, give HRT or the COCP until about 50 to protect bone and heart.

Turner syndrome (45,X and variants)

• Karyotypes: 45,X (about half), isochromosome Xq [46,X,i(Xq)], and mosaics. Loss of the paternal X is usual.
• Gonadal dysgenesis: germ cells reach the ovaries but are lost quickly → streak ovaries, high FSH and LH, low oestradiol → primary amenorrhoea and absent puberty (some mosaics menstruate, then develop premature ovarian insufficiency).
• Short stature (loss of one SHOX gene), webbed neck, low hairline, wide carrying angle (cubitus valgus), broad shield chest with widely spaced nipples, short 4th metacarpals, high-arched palate, lymphoedema of hands and feet at birth (cystic hygroma on antenatal scan).
• Heart: bicuspid aortic valve, coarctation of the aorta, aortic dilatation and dissection (risk rises in pregnancy).
• Kidneys: horseshoe kidney.
• Others: hypothyroidism (autoimmune), diabetes, hypertension, hearing loss, coeliac and inflammatory bowel disease. Intelligence is usually normal.
• Management: growth hormone in childhood; oestrogen to induce puberty, then cyclical HRT; cardiac MRI and echo; fertility usually needs donor eggs (with cardiac review first). If Y chromosome material is found, remove the gonads (gonadoblastoma risk).

Infertility

• Definition: no pregnancy despite 12 months of regular sex without contraception. Investigate earlier if the woman is over 35, has amenorrhoea or oligomenorrhoea, previous PID or pelvic surgery, or a known male problem.
• Primary (never conceived) or secondary (previous conception).
• About 1 in 7 couples are affected. Roughly 80% of couples conceive within a year and 90% within two.
• Causes (approximate shares): male factor about 30%, female factor about 30%, both or other about 15%, unexplained about 25%.

Causes

Investigation of the couple

Woman

• Ovulation: history of regular cycles; mid-luteal progesterone.
• Hormones: early follicular FSH, LH and oestradiol; AMH and antral follicle count (ovarian reserve; fewer than about 4 follicles suggests poor response); prolactin, TSH, testosterone if cycles are irregular.
• Tubes and uterus: hysterosalpingography (HSG) or HyCoSy if low risk; laparoscopy and dye test (gold standard; also treats endometriosis and adhesions) if there is a history of PID, endometriosis or surgery. Screen for chlamydia before instrumenting the uterus.
• Transvaginal ultrasound for fibroids, ovarian morphology and hydrosalpinx.
• Rubella immunity, folic acid, stop smoking, healthy weight.

Man

• Semen analysis after 2–4 days of abstinence; if abnormal, repeat after about 3 months (one cycle of spermatogenesis).
• WHO lower reference limits (2010): volume 1.5 mL, concentration 15 million/mL, total 39 million per ejaculate, progressive motility 32%, normal forms 4%.
• Azoospermia or severe oligospermia: FSH, LH, testosterone, karyotype, Y-chromosome microdeletion testing and CFTR screening.

Treatment

• General: regular intercourse every 2–3 days, healthy weight, stop smoking, folic acid.
• Anovulation: letrozole or clomifene (antioestrogen effect raises FSH); gonadotrophins; pulsatile GnRH or gonadotrophins for hypothalamic causes; dopamine agonist for hyperprolactinaemia; treat thyroid disease.
• Tubal disease: tubal surgery in selected cases; IVF is the main option; remove hydrosalpinges before IVF.
• Male factor: treat reversible causes; intrauterine insemination (IUI) for mild problems; IVF with ICSI for severe oligospermia; surgical sperm retrieval for azoospermia; donor sperm.
• Unexplained: expectant management, then IVF.
• Premature ovarian insufficiency: donor eggs.

Quick revision

• Low sex steroid + high LH/FSH = primary; low/normal LH/FSH = secondary.
• PCOS: 2 of 3 (androgens, anovulation, polycystic ovaries); exclude CAH, Cushing, tumour, prolactin, thyroid.
• PCOS treatment: weight loss, COCP, antiandrogen with contraception, metformin, letrozole/clomifene.
• Kallmann: anosmia + low GnRH; fertility with hCG/FSH or pulsatile GnRH.
• Klinefelter 47,XXY: tall, small firm testes, gynaecomastia, azoospermia, high FSH/LH.
• Turner 45,X: short, webbed neck, streak ovaries, coarctation, bicuspid valve, horseshoe kidney.
• Infertility after 12 months; mid-luteal progesterone 7 days before period; HSG or laparoscopy and dye; semen analysis.
• Exogenous testosterone switches off sperm production.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Gynaecology by Ten Teachers).

FAQ