Reproductive Hormone Disorders

5-alpha-reductase deficiency is an autosomal recessive intersex or “disorder of sex development” (DSD) condition caused by a loss-of-function mutation in a gene on chromosome 2. The affected subjects have a 46,XY karyotype, bilateral testes, and normal testosterone production but have impaired virilization during embryogenesis due to defective conversion of testosterone to dihydrotestosterone (DHT), which is a significantly more potent androgen. This leads to male pseudohermaphroditism or ambiguous genitalia in males. Also known as pseudovaginal perineoscrotal hypospadias, these patients present with a clitoris-like phallus, cryptorchidism, bifid scrotum, and a rudimentary prostate. No Müllerian structures are present.

Klinefelter syndrome is a chromosomal aneuploidy characterized by the presence of 1 or more extra X chromosomes in a male karyotype, most commonly leading to karyotype 47,XXY. Klinefelter syndrome is associated with decreased levels of testosterone and is the most common cause of congenital hypogonadism. Symptoms are often not noticed until adolescence or adulthood. Individuals with this condition tend to present as tall, phenotypic men with small testes, decreased body hair, gynecomastia, and infertility. Treatment consists of life-long testosterone replacement therapy.

Aromatase deficiency is a very rare genetic condition with autosomal recessive inheritance. Aromatase deficiency is characterized by congenital estrogen deprivation with increased levels of testosterone due to decreased levels of the aromatase enzyme. Affected females present with abnormal development of the external genitalia, virilization, primary amenorrhea, and tall stature. Males usually develop symptoms later in life, including hyperinsulinemia and lipid metabolism disorders. Individuals affected by aromatase deficiency have an increased risk of developing osteoporosis. Treatment involves hormone replacement therapy.

Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Hypergonadotropic hypogonadism results when the gonads fail, and hypogonadotropic hypogonadism results from failures in the hypothalamic–pituitary–gonadal axis. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Diagnosis is guided by the history, physical exam, measurement of hormone levels, and an evaluation for an underlying etiology. Management is with hormone replacement.

Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. The work of hormones allows the body to maintain homeostasis and regulate growth and development. Hormones are typically either made from amino acids or derived from cholesterol (the latter group being known as steroid hormones). Hormones exert their effects by binding to receptors either on the cell surface (most amino acid–based hormones) or within the cytosol (steroid hormones). Ultimately, binding to receptors triggers changes in gene expression or enzymatic activity within the cell.

The pituitary gland, also known as the hypophysis, is considered the “master endocrine gland” because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. The pituitary gland has 2 lobes: the anterior lobe (the adenohypophysis) and the posterior lobe (the neurohypophysis). Each lobe has its own regulation, set of secretory products, and feedback loops. Abnormalities in the pituitary gland can lead to a wide range of clinical conditions, some of which include hyperprolactinemia, acromegaly, hyperthyroidism or hypothyroidism, and central diabetes insipidus.

The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Different nuclei within the hypothalamus play roles in hormone regulation and secretion, autonomic regulation, thermoregulation, food and water intake, sleep and circadian rhythms, memory, and emotional behavior. The hypothalamus has both neural and circulatory connections with the pituitary gland. Abnormalities in the hypothalamus can lead to a wide range of clinical conditions.

Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Diagnosis is via physical exam and history. Management is guided by clearly discussing patient expectations after explaining the benefits and risks. Treatment includes conservative management with lifestyle modifications, oral medications, and injectables. Invasive surgical penile implants may be considered when conservative measures fail. Ultimately, both the patient and partner must be in tune with the treatment modalities to optimize their overall satisfaction.

Androgen insensitivity syndrome (AIS) is an X-linked recessive condition in which a genetic mutation affects the function of androgen receptors, resulting in complete (CAIS), partial (PAIS), or mild (MAIS) resistance to testosterone. All individuals with AIS have a 46,XY karyotype; however, phenotypes vary and include phenotypic female, virilized female, undervirilized male, and phenotypic male individuals. Androgen insensitivity syndrome always leads to infertility. Hormone analysis, imaging, and genetic testing help make the diagnosis. Management of AIS varies depending on the degree of androgen sensitivity, phenotype, and gender identity, and may involve hormone-replacement therapy and surgery to correct anatomical anomalies of the reproductive and genital structures.

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%‒10% of women in the age group. Characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction, PCOS increases a woman’s risk for infertility, endometrial hyperplasia or carcinoma, and cardiovascular disease. The pathophysiology is incompletely understood but thought to have a multifactorial genetic basis causing altered pulsatile release of gonadotropin-releasing hormone (GnRH), as well as increases in luteinizing hormone (LH), androgens, estrogen, and insulin: The result is chronic anovulation and hirsutism, which define the condition. Diagnosis is one of exclusion; therefore, other causes of abnormal uterine bleeding and hirsutism must be ruled out. Management includes attempting to restore normal ovulation through weight loss, oral contraceptive pills (OCPs), and fertility assistance.

Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. Both sexes can be affected, although the incidence is much higher in males. The lack of sex hormones results in impaired pubertal development. Characteristically, there is an associated absence or decreased sense of smell (hyposmia or anosmia), which helps differentiate KS from other conditions. The diagnosis is made by hormone levels in blood and brain imaging showing the absence of olfactory structures. Genetic testing may assist in establishing a definite diagnosis. Treatment consists of hormone replacement therapy.

True hermaphroditism, or ovotesticular disorder of sexual development (ODSD), is characterized by the presence of an ovotesticular gonad that contains both ovarian and testicular elements. Individuals are usually born with ambiguous genitalia, but the diagnosis is rarely confirmed before puberty. The most common karyotype is 46,XX, and less often, 46,XY can be identified. Gonadal biopsy with histologic examination confirms the diagnosis. Management needs to consider the individual’s preferences wherever possible. Treatment options range from hormone replacement to surgical removal of part of the ovotestis gonad to improve fertility and to decrease the risk of malignancies.

Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Some cases are pathological or secondary to chronic liver disease, kidney disease, or hyperthyroidism. The majority of cases are asymptomatic and do not need treatment.

Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Those affected may have a host of medical anomalies involving, but not limited to, the cardiac, renal, reproductive, skeletal, and lymphatic systems. Characteristic appearance is that of a woman with short stature, webbed neck, broad chest with widely spaced nipples, low posterior hairline, and peripheral edema of the hands and feet. Genetic testing confirms the diagnosis. Treatment consists of hormone replacement therapy.