A 38-year-old woman comes to the office due to breast tenderness and absence of menstrual periods over the last 3 months. The patient has a history of schizophrenia and familial hypercholesterolemia. Medications include risperidone, which has led to significant improvement in psychotic symptoms, and atorvastatin. BMI is 26 kg/m², down from 30 kg/m² 6 months ago after following a strict dietary plan. Basic serum chemistry panel and thyroid function tests are normal, and urine pregnancy test is negative. Which of the following is the most likely explanation for this patient's amenorrhea?

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11ec160b_3c4b_e270_9249_9578b0663712_MD0001_00 This patient with amenorrhea and breast tenderness likely has drug-induced hyperprolactinemia due to risperidone, an antipsychotic drug used in the management of schizophrenia. Its primary action is to inhibit dopamine D2 receptors, but it also has inhibitory effects on serotonergic and alpha-adrenergic pathways. Secretion of prolactin from the anterior pituitary is primarily regulated by the inhibitory effect of hypothalamic dopamine; stimulation of D2 receptors on lactotrophs decreases the synthesis and release of prolactin. Because risperidone and other antipsychotic drugs block D2 receptor activation, there is a loss of the normal tonic inhibition of prolactin release, leading to hyperprolactinemia in some cases. This can result in galactorrhea and breast soreness. In addition, elevated prolactin levels inhibit release of gonadotropin-releasing hormone from the hypothalamus, resulting in central hypogonadism and amenorrhea. (Choice A) Nonclassic 21-hydroxylase deficiency may be associated with menstrual irregularity (most often oligomenorrhea), hirsutism, and acne in women. Nonclassic 21-hydroxylase deficiency most often presents in childhood or adolescence. (Choice B) Asherman syndrome refers to the presence of severe intrauterine adhesions that cause amenorrhea and infertility. It typically occurs in patients who have had multiple dilation and curettage procedures or those with chronic endometritis. (Choice D) Polycystic ovary syndrome is characterized by infertility, oligomenorrhea, and hyperandrogenism. It typically begins in adolescence and is unlikely to develop in a 38-year-old woman. Most patients with polycystic ovary syndrome are obese. Insulin resistance is thought to play a central role in its pathogenesis. (Choice E) Primary ovarian insufficiency is characterized by amenorrhea, hypoestrogenism, and elevated serum gonadotropin levels in women age <40. The decreased estrogenic effect on breast tissue can cause a decline in breast density but would not cause tenderness. (Choice F) Severe weight loss (eg, anorexia nervosa), intense exercise, and/or severe stress can cause amenorrhea by inducing functional hypothalamic amenorrhea. However, none of these would cause breast tenderness. Educational objective: The secretion of prolactin is controlled by the inhibitory effect of hypothalamic dopamine. Risperidone and other antipsychotics cause hyperprolactinemia by blocking D2 receptors on lactotrophs. Elevated prolactin leads to amenorrhea (inhibition of gonadotropin-releasing hormone release), galactorrhea, and breast soreness. __________ References: Antipsychotic-induced hyperprolactinemia: synthesis of world-wide guidelines and integrated recommendations for assessment, management and future research. (http://www.ncbi.nlm.nih.gov/pubmed/28889207) Clinical management of antipsychotic-induced hyperprolactinemia. (http://www.ncbi.nlm.nih.gov/pubmed/25772527)

A 38-Year-Old Woman Comes to the Office Due to Breast