Deviations

When the HPG axis goes wrong, the pattern of the blood hormones — LH, FSH, testosterone, and inhibin B — usually points to where in the cascade the problem sits. The diagnostic framework rests directly on the axis’s architecture: each tier has a characteristic signature when it fails, and the feedback loops make those signatures distinct.

The four levels

Most disorders can be localized to one of four levels:

1. Upstream regulation — the inputs to the axis: energy status, stress, prolactin, thyroid hormone, opioids, chronic illness. Disturbances here produce functional hypogonadism, usually reversible.
2. Hypothalamic GnRH neurons — their existence, migration, or signaling. Disturbances here produce congenital hypogonadism in its various molecular forms.
3. Pituitary gonadotropes — their ability to receive GnRH and produce LH and FSH. Disturbances here often involve broader pituitary disease.
4. Gonads — the testes’ or ovaries’ ability to respond to LH and FSH. Disturbances here are primary hypogonadism.

The level affected determines the lab signature.

The two-pattern split

The single most useful initial distinction is between central and primary hypogonadism — and it is read directly from LH and FSH.

Pattern	LH	FSH	Testosterone	What it points to
Hypergonadotropic (primary)	high	high	low	Gonads can’t respond; pituitary cranks up the drive. Levels 4 only.
Hypogonadotropic (central)	low	low	low	No upstream signal reaching the gonads. Levels 1, 2, or 3.
LH-preferential dissociation	low	normal	low	Slow GnRH pulses — functional, genetic (classically TAC3/TACR3), or selective gonadotrope damage. See below.
Delayed but normal	low → rising	low → rising	low → rising	Constitutional delay; the axis is on a late but normal timeline.
Selective FSH rise	normal	high	normal	Sertoli-cell dysfunction with preserved Leydig function (loss of inhibin B).

Everything after this initial split is about narrowing further within the chosen pattern.

The LH-preferential pattern (LH/FSH dissociation)

A specific signature within the central pattern: low LH with normal or near-normal FSH in the face of low testosterone. LH and FSH come from the same gonadotrope cells and are driven by the same GnRH pulses, so they normally rise and fall together. When they dissociate, the underlying physiology points in a specific direction.

The pulse-frequency principle

LH and FSH respond differently to GnRH pulse frequency:

• Fast GnRH pulses (~one per hour) → preferentially stimulate LH production.
• Slow GnRH pulses (every 3+ hours) → preferentially stimulate FSH production.

The mechanism sits at the level of β-subunit gene transcription: the LH-β gene needs rapid, repeated GnRH signaling to be transcribed efficiently, while the FSH-β gene is more sensitive to any pulses, including slow ones. (The same physiology underlies pharmacologic GnRH-agonist suppression like leuprolide: continuous GnRH eventually shuts both off, but along the way FSH lingers longer than LH.) See pulsatility for the underlying pulse generator.

The clinical corollary: anything that slows the GnRH pulse generator produces a low-LH / preserved-FSH pattern.

Causes that slow the pulse generator

The differential cuts across the four-level framework:

• Functional (Level 1) — energy deficit (undernutrition, athletic training, eating disorders), chronic opioid use, hyperprolactinemia, chronic illness, sustained stress. The most common acquired causes and the first to screen for; many are reversible.
• Genetic / KNDy network (Level 2) — the prototype is TAC3 / TACR3 mutations (neurokinin B and its receptor), where the pulse generator fires too slowly because the frequency-driving NKB component is missing. Often produces this signature in textbook form; notable for a high rate (~20–30%) of spontaneous reversal in adulthood. Partial GNRHR, GNRH1, KISS1R, and FGFR1 variants can also present this way.
• Selective gonadotrope damage (Level 3) — pituitary trauma (especially stalk shearing from head injury), tumors, infiltrative disease (hemochromatosis classically affects gonadotropes preferentially), cranial radiation.
• Exogenous suppression — anabolic steroid or testosterone therapy produces strong negative feedback that often hits LH harder than FSH on labs. The clinical fingerprint is large muscles with small (disused) testes.

A normal-physiology mimic

One important non-pathologic explanation: the FSH-first pattern of early puberty. FSH characteristically rises before LH at the onset of gonadarche, exactly because the awakening pulse generator produces slow pulses first. A boy in early Tanner G2/G3 with low LH and rising-but-still-normal FSH may simply be in his own normal pre-LH phase. The discriminator is time: rising LH on follow-up over 3–6 months = early gonadarche resolving; stable low LH = committed partial deficit. See gonadarche for the underlying timing.

Narrowing within this bucket

Beyond the general workup (see How the workup reasons, below), a few discriminators are specifically informative for the LH-preferential pattern:

• Anabolic-steroid history — ask directly; the muscle-bulk-with-small-testes mismatch is the physical tell.
• Inhibin B and AMH — preserved values support partial CHH or CDGP-like physiology with intact Sertoli function; low values argue for a more global deficit.
• Genetic CHH panel — TAC3 / TACR3 are particularly high-yield given this lab signature.
• Pituitary MRI — selective stalk thinning, post-traumatic findings, or hemosiderin (e.g., hemochromatosis) point to Level 3 damage as the cause.
• Time — observation over 3–6 months distinguishes an awakening axis from a committed partial deficit. In adolescents this is often the single most useful “test.”

Functional suppression (Level 1)

The HPG axis is intact but suppressed by something outside it. This is the largest and most reversible category, and identifying it before extensive workup is the first goal.

• Energy deficit — chronic undernutrition, eating disorders, severe endurance training, rapid weight loss. Mechanism: low leptin → reduced kisspeptin signaling → suppressed GnRH pulsatility.
• Hyperprolactinemia — prolactinoma, antipsychotic or antiemetic medications, primary hypothyroidism, chronic stress or nipple stimulation. Mechanism: prolactin directly suppresses GnRH.
• Hypothyroidism — multiple mechanisms including direct GnRH effects and secondary hyperprolactinemia.
• Glucocorticoid excess — Cushing syndrome or chronic steroid therapy. Cortisol suppresses GnRH at multiple levels.
• Chronic illness — IBD, celiac, cystic fibrosis, chronic kidney disease, poorly controlled diabetes, severe inflammation. Combined effect of cytokines, undernutrition, and medications.
• Opioids — chronic opioid use directly suppresses GnRH.
• Anabolic-steroid use — exogenous testosterone produces low LH/FSH (via negative feedback) with normal or high testosterone on labs but small testes from disuse. See testosterone therapy and axis recovery for the spectrum from physiologic-dose TRT to abuse and for what recovery looks like after cessation.

The initial workup of any unexplained low-testosterone state therefore includes prolactin, TSH and free T4, basic chemistry, CBC, inflammatory markers, celiac screen, and a careful medication and lifestyle history — because identifying a functional cause is potentially curative without further endocrinology.

Prognosis for functional cases is excellent once the underlying cause is corrected; the axis usually resumes within weeks to months.

Congenital hypogonadism — GnRH neuron problems (Level 2)

If functional causes are ruled out and LH and FSH are inappropriately low, the issue lies at the hypothalamic or pituitary level. The single largest category is congenital hypogonadotropic hypogonadism (CHH) — a developmental failure of the GnRH-neuron system, often genetic, present from birth but typically presenting clinically as failure to enter puberty.

CHH is divided by mechanism:

• Kallmann syndrome — CHH plus anosmia or hyposmia (a reduced sense of smell). The combination reflects the shared embryonic origin of GnRH neurons and olfactory neurons: when the migration fails, both are affected. Caused by mutations in ANOS1 (X-linked recessive), FGFR1, FGF8, PROK2, PROKR2, CHD7, SEMA3A, and others. Variable expressivity is common — the same mutation can produce full Kallmann in one relative and a mild delay in another.
• Normosmic CHH — CHH with intact sense of smell. The migration succeeded but the resulting GnRH circuit is non-functional. Caused by mutations in the GnRH or kisspeptin signaling pathways: GNRH1, GNRHR, KISS1, KISS1R, TAC3, TACR3.
• Partial CHH — incomplete forms with preserved minipuberty, partial pubertal initiation, or selective deficits (such as LH-preferential deficiency from slow GnRH pulse frequency). Better prognosis than complete CHH, and some variants (especially TAC3 / TACR3) show 20–30% rates of spontaneous reversal in adulthood.

Diagnostic clues:

• Anosmia points to the Kallmann subtype — sense of smell is worth testing formally because patients often do not realize it is impaired.
• Cryptorchidism or micropenis at birth indicates failed minipuberty, suggesting a severe (complete) congenital deficit.
• Family history with X-linked, autosomal-dominant, or autosomal-recessive patterns informs which genes are most likely.
• Genetic CHH panels identify a causative variant in roughly 50% of cases.

Treatment can be hormone replacement (testosterone or estradiol/progesterone), gonadotropin therapy (which preserves testicular function and fertility), or pulsatile GnRH (the most physiologic option, requiring a portable pump).

Pituitary problems (Level 3)

If gonadotropins are low because the pituitary itself is failing, the picture often involves other pituitary deficits as well — making this category distinct from isolated GnRH-neuron failure.

• Pituitary tumors — adenomas, craniopharyngioma, Rathke cleft cyst. Compress gonadotropes selectively or affect multiple cell types.
• Pituitary apoplexy — sudden hemorrhage or infarction.
• Infiltrative disease — sarcoidosis, hemochromatosis (iron deposits selectively damaging gonadotropes), hypophysitis (autoimmune).
• Cranial radiation — for childhood cancer or head/neck tumors; effects often delayed by years.
• Post-traumatic hypopituitarism — stalk shearing or basilar skull fracture damaging the pituitary or its blood supply.
• Congenital pituitary hypoplasia — usually with combined pituitary hormone deficiency from the start.
• Rare hormone-subunit defects — LHB or FSHB mutations producing isolated LH or FSH deficiency.

Clues that point here rather than to GnRH-neuron failure: other axis problems (low cortisol, low thyroxine, abnormal prolactin), structural findings on pituitary MRI, and a history of trauma, radiation, or systemic disease.

Primary gonadal failure (Level 4)

When the testes or ovaries themselves cannot respond, the pituitary cranks up its drive — producing the hypergonadotropic pattern of high LH and FSH with low testosterone or estradiol. This signature is unmistakable on labs.

In males:

• Klinefelter syndrome (47,XXY) — the most common chromosomal cause, affecting roughly 1 in 600 male births and often underdiagnosed. Tall stature, small firm testes (typically under 6 mL even in adulthood), gynecomastia, infertility, and sometimes learning differences. Diagnosed by karyotype.
• Other chromosomal causes — XX male syndrome, mixed gonadal dysgenesis, 47,XYY with later failure.
• Prior testicular damage — testicular torsion (especially bilateral), trauma, severe orchitis (mumps), chemotherapy, or radiation.
• Untreated cryptorchidism — testes left in the abdomen are progressively damaged by the higher temperature.
• Anorchia — congenitally absent testes (“vanishing testes” syndrome).
• Genetic syndromes — Noonan syndrome and myotonic dystrophy can cause primary testicular failure as part of a broader phenotype.

In females:

• Turner syndrome (45,X) — the chromosomal counterpart; streak ovaries, primary amenorrhea, short stature, and a range of associated features.
• Premature ovarian insufficiency — exhaustion of the ovarian follicle pool before age 40, from genetic, autoimmune, iatrogenic (chemotherapy, radiation, oophorectomy), or idiopathic causes.

Treatment is typically lifelong hormone replacement. Fertility is sometimes achievable with assisted reproductive techniques (in Klinefelter, via microsurgical testicular sperm extraction; in premature ovarian insufficiency, usually only via donor eggs).

Constitutional delay of growth and puberty (CDGP)

A distinct category worth flagging: the most common cause of pubertal delay is not a disorder of the axis at all but constitutional delay — the “late bloomer.” The HPG axis is normal, simply running on a delayed schedule, often with a strong familial pattern. Bone age is delayed but matches height age; puberty starts spontaneously, just later than peers; adult height and fertility are normal.

The diagnostic challenge is that CDGP looks identical to mild CHH at presentation — both show low LH, FSH, and testosterone in a boy who hasn’t entered puberty. Inhibin B and AMH tend to be more preserved in CDGP than in CHH but with substantial overlap. Definitive distinction is often retrospective: if puberty starts spontaneously, it was CDGP; if it hasn’t by 18 years of age, the diagnosis shifts to CHH.

How the workup reasons

The diagnostic flow follows the framework above:

1. Confirm the deficit. Tanner staging, testicular volume, growth assessment, basic hormones with morning timing.
2. Central or primary? Read LH and FSH against testosterone.
3. If central: screen functional causes. Prolactin, TSH/free T4, basic chemistry, CBC, inflammatory markers, celiac screen, medication and lifestyle history.
4. If still unexplained and central: characterize further. Sense of smell (Kallmann?), neonatal history (minipuberty intact?), syndromic features, family history. Pituitary MRI with attention to olfactory bulbs and stalk.
5. Genetic testing for confirmed congenital cases. CHH gene panel.
6. Ambiguous CDGP vs CHH: inhibin B, AMH, and time — observe whether the axis starts to move on its own.

For the longitudinal side of step 6 — what to measure at each follow-up, at what frequency, and which trends to anchor against — see tracking the awakening axis in the gonadarche chapter.

When the basal pattern is ambiguous — most often the CDGP-versus-CHH overlap of step 6, or a single low LH that might merely be a pulse trough — provocative testing stimulates the axis directly to reveal its capacity to respond, which no static measurement can show. A GnRH or GnRH-agonist challenge asks whether the pituitary can make LH and FSH on demand; an hCG challenge asks whether the testes can make testosterone; the result separates a merely quiet axis from a genuinely deficient one.

Key idea

Disorders of the HPG axis are read as patterns, not as single numbers. The architecture of the axis — three tiers, three feedback loops, an integrative pulse generator — produces a small set of recognizable signatures, and the diagnosis is, in effect, an inverse problem: given this signature, which part of this architecture has failed?