Can you provide a concise hormonal knowledge base summarizing the major endocrine axes, their hormones, physiological actions, and common clinical conditions with treatment guidelines?

Hormonal Knowledge Base: Major Endocrine Axes

Overview of Hypothalamic-Pituitary Regulation

The hypothalamic-pituitary system functions as the master regulator of endocrine homeostasis, consisting of distinct anterior and posterior pituitary systems that control thyroid, adrenal, gonadal, and growth axes through releasing hormones and negative feedback loops. 1

Anterior Pituitary Hormones and Target Organs

The anterior pituitary contains five specialized cell types that produce distinct hormones 1, 2:

• Thyrotropes produce thyroid-stimulating hormone (TSH), which regulates thyroid function and should be measured to assess thyroid axis integrity 1
• Corticotropes secrete adrenocorticotropic hormone (ACTH), controlling cortisol production from the adrenal cortex 2
• Gonadotropes release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), governing reproductive function 2
• Somatotropes produce growth hormone (GH), regulating growth and metabolism 2
• Lactotropes secrete prolactin, controlling lactation and reproductive processes 2

Posterior Pituitary Hormones

The posterior pituitary releases two critical hormones synthesized in the hypothalamus 1:

• Oxytocin regulates uterine contractions during labor and milk ejection during breastfeeding 1
• Vasopressin (antidiuretic hormone/ADH) controls water balance and blood pressure 1

Hypothalamic-Pituitary-Thyroid (HPT) Axis

Physiologic Regulation

The HPT axis operates through negative feedback: thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates TSH release, which drives thyroid production of T3 and T4, which then inhibit further TRH and TSH secretion 1.

Clinical Evaluation

When evaluating thyroid dysfunction, always measure both TSH and free T4 (FT4) simultaneously in symptomatic patients, as TSH alone can miss central hypothyroidism where TSH remains falsely normal despite low FT4. 3

• Low TSH with low FT4 indicates central (secondary) hypothyroidism from pituitary or hypothalamic disease 3
• High TSH with low FT4 indicates primary hypothyroidism from thyroid gland failure 3
• Low TSH with high FT4 indicates hyperthyroidism 3

Treatment Principles for Hypothyroidism

For primary hypothyroidism with TSH persistently >10 mIU/L or symptomatic patients with any TSH elevation 3:

• Initiate thyroid hormone supplementation 3
• Monitor TSH every 6-8 weeks during dose titration, targeting TSH within reference range 3
• FT4 can guide therapy when TSH normalization lags behind clinical improvement 3

Critical safety point: In patients with suspected panhypopituitarism or central hypothyroidism, NEVER start thyroid hormone replacement before ensuring adequate cortisol replacement, as increased cortisol metabolism from thyroid hormone can precipitate life-threatening adrenal crisis. 3

Hypothalamic-Pituitary-Adrenal (HPA) Axis

Diagnostic Approach to Adrenal Insufficiency

Distinguishing primary from secondary adrenal insufficiency requires simultaneous measurement of morning cortisol and ACTH, as this localization determines appropriate treatment and prevents dangerous errors in hormone replacement. 3

• Low morning cortisol with low ACTH indicates secondary (central) adrenal insufficiency from pituitary/hypothalamic disease 3
• Low morning cortisol with elevated ACTH indicates primary adrenal insufficiency (Addison's disease or adrenal hemorrhage) 3
• Morning serum samples are mandatory for accurate interpretation 3

Prevalence in Pituitary Disease

In patients with nonfunctioning pituitary adenomas, adrenal insufficiency occurs in 17-62% of cases, making it the third most common hormonal deficit after growth hormone and gonadotropin deficiency 3.

Treatment Considerations

Replacement for adrenal insufficiency must be initiated preoperatively in all patients with confirmed deficiency 3.

Hypothalamic-Pituitary-Gonadal (HPG) Axis

Physiologic Regulation

The HPG axis involves gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulating pituitary FSH and LH release, which then act on gonads to produce sex steroids and regulate fertility 1.

Diagnostic Evaluation in Men

For suspected male hypogonadism, measure morning total testosterone levels along with LH and FSH to distinguish primary from secondary hypogonadism, as this classification fundamentally determines whether fertility preservation is possible. 3

Calculate LH and FSH based on three measurements taken 20 minutes apart between specific cycle days for accuracy 3:

• LH/FSH ratio >2 suggests polycystic ovary syndrome (PCOS) 3
• FSH >35 IU/L indicates primary gonadal failure 3
• Low LH (<7 IU/mL) suggests secondary (central) hypogonadism 3

Diagnostic Evaluation in Women

For women with suspected reproductive endocrine disorders, comprehensive evaluation includes 3:

• Menstrual history: Document cycle length (normal 23-35 days), bleeding duration, and regularity for at least 6 months 3
• LH and FSH: Measured on cycle days 3-6 3
• Prolactin: Morning resting levels (not post-ictal), with >20 μg/L considered elevated 3
• Mid-luteal progesterone: <6 nmol/L indicates anovulation 3
• Testosterone: >2.5 nmol/L on cycle days 3-6 suggests hyperandrogenism 3
• Pelvic ultrasonography: Transvaginal approach is more sensitive than transabdominal for detecting ovarian pathology 3

Treatment Principles

For secondary hypogonadism in men desiring fertility, gonadotropin therapy (hCG with FSH) is the standard treatment, as testosterone replacement therapy is absolutely contraindicated because it suppresses the HPG axis and eliminates spermatogenesis. 3

For functional hypogonadism associated with obesity 3:

• Weight loss through low-calorie diets can reverse obesity-associated secondary hypogonadism 3
• Physical activity provides similar benefits, with results correlating to exercise duration and weight loss 3
• Testosterone increases from lifestyle modification alone are modest (1-2 nmol) 3
• Combined lifestyle changes with testosterone therapy may yield superior outcomes in symptomatic patients 3

Special Condition: Hyperlutealis

The American College of Obstetricians and Gynecologists defines hyperlutealis as excessive ovarian stimulation from markedly elevated hCG or LH, causing bilateral ovarian enlargement with multiple theca-lutein cysts 4.

Do not confuse hyperlutealis with isolated polycystic ovaries: hyperlutealis presents with marked bilateral ovarian enlargement (often >10 cm), symptoms, and significantly elevated androgens, whereas isolated polycystic ovaries show only ultrasound changes without symptoms or hormonal abnormality. 4

The pathophysiology involves 4:

• Overstimulation of the HPG axis through excessive gonadotropin exposure 4
• Accelerated GnRH secretion driving excessive LH production 4
• LH hypersecretion directly stimulating ovarian theca stromal cells 4
• Insulin resistance and hyperinsulinemia amplifying the ovarian response to gonadotropins 4

Hyperlutealis typically resolves spontaneously after removal of the gonadotropin stimulus (e.g., delivery of pregnancy), unlike PCOS which requires long-term management 4.

Growth Hormone Axis

Prevalence of Deficiency

In patients with nonfunctioning pituitary adenomas, growth hormone deficiency is the most common hormonal deficit, affecting 61-100% of patients 3.

Diagnostic Evaluation

Routine insulin-like growth factor 1 (IGF-1) evaluation is recommended in all patients with suspected nonfunctioning pituitary adenomas to rule out GH hypersecretion that might not be clinically suspected 3.

Prolactin Regulation

Clinical Evaluation

Routine prolactin testing is recommended in all patients with suspected pituitary disease to rule out hypersecretion that may not be clinically apparent, but never measure prolactin post-ictally as seizures transiently elevate levels. 3

In nonfunctioning pituitary adenomas, hyperprolactinemia occurs in 25-65% of patients, with mean levels around 39 ng/mL and minority exceeding 200 ng/mL 3.

Diagnostic Considerations

Galactorrhoea (crusting on nipples or expression of breast milk in non-lactating women) warrants 3:

• Assessment of menstrual regularity 3
• Evaluation for hirsutism and signs of hypothyroidism 3
• Pituitary MRI if prolactin levels or clinical features suggest hypothalamic-pituitary pathology 3

Comprehensive Pituitary Evaluation

Screening Recommendations

Routine endocrine evaluation of all anterior pituitary axes is recommended in patients with suspected pituitary disease because the prevalence of deficits exceeds clinical suspicion for all axes, and replacement thresholds differ in panhypopituitarism versus isolated deficiencies. 3

In nonfunctioning pituitary adenomas 3:

• Overall hypopituitarism prevalence: 37-85% 3
• Panhypopituitarism: 6-29% 3
• Central hypogonadism: 36-96% 3
• Central hypothyroidism: 8-81% 3
• Diabetes insipidus: Only 7% at presentation 3

Imaging Recommendations

Pituitary MRI is indicated when clinical features (galactorrhoea) or laboratory results (hyperprolactinemia) suggest hypothalamic-pituitary axis abnormality, though small lactotroph adenomas may escape detection beyond MRI resolution 3, 1.

Energy Availability and Reproductive Function

Low Energy Availability in Female Athletes

Energy availability (EA) is calculated as: [Energy intake - Exercise energy expenditure] / Fat-free mass per day 3.

EA of 30 kcal/kg FFM·day⁻¹ discriminates between amenorrheic versus eumenorrheic status, though it does not distinguish subclinical disturbances, and there is a linear relationship between EA and menstrual disturbances rather than a binary threshold. 3

Low EA disrupts LH pulsatility (a surrogate for GnRH pulsatility), which disturbs gonadotropin release and causes menstrual dysfunction manifesting as oligo-amenorrhea 3.