Review Question - QID 216416

This patient who presents with infertility, normal external genitalia, normal luteinizing hormone (LH), normal testosterone, and increased follicle-stimulating hormone (FSH) likely has decreased inhibin B levels caused by reduced production in Sertoli cells. Inhibin B normally leads to decreased FSH production; high levels of FSH often indicate decreased production of inhibin B.

Sertoli cells are sustentacular cells in the seminiferous tubule of the testes which aid in spermatogenesis by secreting various hormones, forming the blood-testis barrier, and maintaining the spermatogonial stem cell niche. FSH is secreted from the anterior pituitary gland and stimulates the release of inhibin B, a dimeric protein complex from Sertoli cells that exerts both an exocrine and paracrine effect. Inhibin B downregulates FSH synthesis and inhibits FSH secretion, exerting a negative feedback effect on the hypothalamic-pituitary axis (HPA). Inhibin B may also act locally to regulate spermatogenesis. Multiple studies have conclusively shown the inverse relationship between FSH and inhibin B levels, with low levels of inhibin B being associated with high levels of FSH. Unfortunately, there is no medical therapy for patients with eugonadal infertility; however, many of these patients can still conceive using assisted reproductive technologies.

Makanji et al. provide a review of the discovery, structure, physiology, and clinical applications of inhibins. The authors discuss the function of inhibin in male reproductive physiology in the sections "Inhibins and the male reproductive axis" and "Male reproductive function." The authors recommend further study of inhibin as a potential diagnostic marker for reproductive function.

Incorrect Answers:
Answer 1: Activin is a hormone that generally enhances FSH biosynthesis and secretion in women. In men, the effect of activin on FSH levels is not well-characterized; however, activin is known to largely act via autocrine and paracrine mechanisms and not through endocrine signaling. By contrast, decreased levels of inhibin B are definitively known to be consistent with this patient’s laboratory findings.

Answer 2: Dihydrotestosterone (DHT) is largely synthesized from testosterone in the skin and the liver by the enzyme 5-alpha-reductase. Decreased DHT may be seen in 5-alpha reductase deficiency, which usually presents with undervirilized male external genitalia or ambiguous external genitalia at birth. Decreased levels of DHT are not directly associated with increased FSH production.

Answer 4: Sex hormone-binding globulin (SHBG) is a protein that avidly binds gonadal steroids. SHBG concentration is decreased by obesity, exogenous testosterone, and increased age. In hypogonadal men, such as this patient, SHBG concentrations would be expected to be increased, not decreased. Fluctuations in SHBG levels in normal men usually are functionally silent as the HPA responds to changes in free, not total testosterone.

Answer 5: Steroidogenic acute regulatory (StAR) protein transfers cholesterol from the outer to the inner membrane of the mitochondria in Leydig cells. StAR protein is the rate-limiting step of steroid hormone production in the testes. In a patient with normal testosterone, decreased levels of StAR would not be expected.

Bullet Summary:
In men, inhibin B is synthesized by Sertoli cells in the testes and directly inhibits the secretion of follicle-stimulating hormone (FSH) from the anterior pituitary.