Reproductive & Bone Endocrinology (Clinical)

Polycystic ovary syndrome and hirsutism

Rotterdam needs 2 of 3. PCOS is diagnosed with any two of: oligo- or anovulation, clinical or biochemical hyperandrogenism (hirsutism, acne, high testosterone), and polycystic ovaries on ultrasound. It is a diagnosis of exclusion, so first rule out the mimics: thyroid disease, prolactinoma, nonclassic CAH (17-hydroxyprogesterone), and Cushing syndrome.

Insulin resistance drives androgens. PCOS features insulin resistance and an elevated LH:FSH ratio; high LH and insulin push ovarian theca cells to overproduce androgens, and ovulation fails. Associations are obesity, type 2 diabetes, metabolic syndrome, obstructive sleep apnea, and endometrial hyperplasia or cancer from unopposed estrogen, since anovulatory cycles lack progesterone.

Management by goal.

• Everyone: weight loss is first-line and can restore ovulation; screen for diabetes and dyslipidemia.
• Not seeking pregnancy: a combined OCP regulates cycles, protects the endometrium, and treats hirsutism; add spironolactone for hirsutism, with reliable contraception.
• Insulin resistance: metformin for the metabolic features.
• Seeking pregnancy: letrozole, an aromatase inhibitor, is first-line ovulation induction and beats clomiphene on live births (PPCOS II).

Hirsutism workup. Measure total testosterone and DHEAS, and add 17-hydroxyprogesterone to screen for nonclassic 21-hydroxylase deficiency (CAH). Tempo matters most: gradual peripubertal hirsutism suggests PCOS (the most common cause) or idiopathic hirsutism. Rapid onset with virilization (deepening voice, clitoromegaly, temporal balding) signals a tumor. Testosterone >150–200 ng/dL points to an ovarian tumor (such as a Sertoli-Leydig cell tumor), while a high DHEAS (>700 μg/dL) points to an adrenal tumor; image the ovaries or adrenals accordingly.

Male hypogonadism

Localize with gonadotropins. Check a morning total testosterone (confirmed on a repeat morning sample), LH, FSH, and prolactin. Primary (testicular) failure gives low testosterone with HIGH LH/FSH; the classic cause is Klinefelter syndrome (47,XXY), with tall stature, long limbs, small firm testes, gynecomastia, and infertility. Secondary (central) hypogonadism gives low testosterone with LOW or inappropriately normal LH/FSH, as in Kallmann syndrome (failed GnRH neuron migration, with anosmia) and prolactinoma.

Exogenous testosterone suppresses LH, FSH, and spermatogenesis, so it is the wrong choice for a man who wants to father children.

Osteoporosis: diagnosis and screening

Definition. Osteoporosis is a DEXA T-score ≤ −2.5 at the spine, hip, or femoral neck, OR any fragility (low-trauma) fracture regardless of score. Osteopenia is −1.0 to −2.5. The T-score compares with young adults; the Z-score compares with age-matched peers and is used in younger patients.

Screening. DEXA for all women ≥65 and for postmenopausal women under 65 at increased risk on a formal risk tool such as FRAX (USPSTF 2025). For men, USPSTF finds the evidence insufficient; BHOF and the Endocrine Society advise DEXA for men ≥70, and for men 50 to 69 with risk factors. FRAX estimates 10-year fracture risk from clinical factors and BMD.

Baseline for everyone. Calcium 1000–1200 mg/day and vitamin D 800 IU/day, weight-bearing exercise, fall prevention, and stopping smoking and excess alcohol. These are adjuncts, not a substitute for pharmacotherapy in established osteoporosis.

Osteoporosis pharmacotherapy

Bisphosphonates are first-line. Alendronate, risedronate, and zoledronic acid inhibit osteoclast farnesyl pyrophosphate synthase. Oral doses are taken upright and fasting with a full glass of water, and the patient sits or stands 30–60 minutes afterward to prevent erosive esophagitis. Adverse effects are pill esophagitis, osteonecrosis of the jaw, and atypical femoral fractures. Avoid if CrCl <30–35.

Beyond bisphosphonates. Denosumab is second-line or for high-risk patients and has no renal dose cutoff, but stopping it causes rebound vertebral fractures. An FDA boxed warning (2024) flags severe hypocalcemia in advanced CKD (eGFR under 30 or dialysis), so exclude CKD-MBD first and monitor calcium after dosing. Anabolic agents for severe disease stimulate osteoblasts and are followed by an antiresorptive to keep the gain. Raloxifene, a SERM, also lowers breast cancer risk.

Secondary osteoporosis and Paget disease

Look for a secondary cause in men, premenopausal women, or unexpectedly severe disease: hyperthyroidism, primary hyperparathyroidism, Cushing syndrome or glucocorticoids, hypogonadism, multiple myeloma, celiac disease or other malabsorption, CKD, and alcohol. Glucocorticoids are the most common drug cause.

Paget disease of bone is disordered remodeling: excessive osteoclast resorption followed by chaotic osteoblast repair, leaving thick but weak mosaic lamellar bone. Labs show an isolated high alkaline phosphatase with NORMAL calcium and phosphate. Features are bone pain, skull enlargement (the hat no longer fits), hearing loss, bowed tibia, and high-output heart failure from hypervascular bone. The feared complication is osteosarcoma. Treat symptomatic disease with bisphosphonates.

New sudden pain or a soft-tissue mass in known Paget disease raises alarm for osteosarcoma.