Osteopenia and primary amenorrhea: Are those ovaries on the scan?

Issue: August 2009

ByBeth M. Kaplan, MD

ByStephanie L. Lee, MD, PhD, ECNU

The patient is a 51-year-old woman referred to the endocrinology clinic for the treatment of progressive osteopenia. Her osteopenia was first diagnosed at the early age of 45 with a lumbar spine bone density T-score of –2.18. Her lumbar spine T-score continued to decrease while on raloxifene therapy (60 mg) to –2.77 prior to the endocrine referral. She had a past medical history of HIV on HAART therapy with a CD4 count of 737 cells/mcL and undetectable viral load. She also had a two-year history of type 2 diabetes. Family history was significant for sickle cell anemia and type 2 diabetes and negative for osteoporosis. Her medications included nelfinavir, emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg (Truvada, Gilead), calcium carbonate, raloxifene therapy, vitamin D and conjugated estrogen cream. She did not drink alcohol or use tobacco or illicit drugs. She was never married and had never been pregnant. She denied height change, fracture history or kidney stones. On further questioning she revealed that she had primary amenorrhea and never knew why. She had no previous surgeries and was not shorter than her siblings. She was sexually active with good libido and no dyspareunia. She did have vaginal dryness that was managed with estrogen cream. After further questioning, her maternal aunt and several maternal cousins have primary amenorrhea.

Beth M. Kaplan

Stephanie Lee

On physical exam, her height was 61.5 in, weight 70 kg, BMI 28, blood pressure 131/76 mm Hg and pulse 79. She was a beautiful woman with clear skin who appeared younger than her stated age. She did not have a webbed neck or thyroid abnormalities. Her cardiac, pulmonary and abdominal exams were unremarkable. There was absence of any axillary and pubic sexual hair. Her breast exam was normal for an adult female; she did not have widely spaced nipples or galactorrhea. On pelvic exam, her labia majora and minora were present with small clitoris and a blind vaginal pouch. She did not have palpable ovaries, cervix or uterus. There were no inguinal masses or hernias noted.

Her labs showed an estradiol level ≤37 pg/mL, luteinizing hormone 45.3 miu/mL (15.9–54) follicle-stimulating hormone 38.3 miu/mL (23-116), testosterone 210 ng/dL (14-76), dehydroepiandrosterone sulfate 135 ug/dL (14-180), dihydrotestosterone (DHT) 13 ng/dL (5-30), anti-Müllerian hormone (AMH) 55 ng/mL (0-6.9), androstenedione 57 ng/dL (20-75), prolactin 4.9 ng/mL (2.8-26.7) and progesterone 1 ng/mL. Blood karyotype was 46 XY.

She had an MRI with contrast that showed absence of the uterus and cervix. Soft tissue structures were seen within the pelvis; the report interpreted the structures as likely atrophic ovaries (Figure 1). The right mass measured 2.1 x 1.2 x 1.6 cm and the left mass measured 1.3 x 0.6 x 0.8 cm. No pelvic lymphadenopathy was noted.

Complete Androgen Insensitivity Syndrome (CAIS) is a rare X-linked disorder that is most often due to an androgen receptor (AR) gene mutation. It leads to the failure of normal masculinization of external genitalia in genetic male, XY, individuals. There are more than 300 mutations of the AR. Two-thirds of reported cases have mutations in the C-terminal ligand-binding domain of the AR. Twenty percent of the AR mutations are located in the DNA-binding domain, which results in an AR that cannot bind DNA and modify gene expression. The degree of virilization is determined by the degree of residual AR function, which can be partial or complete. Complete androgen insensitivity results in a phenotypic female, a partial AIS will result in ambiguous genitalia and minor AIS results in an infertile male.

Figure 1: T2-weighted MRI images of the pelvis.
Figure 1. T2-weighted MRI images of the pelvis. A: Sagittal T2-weighted image. B: Coronal T2-weighted image. C: Axial T2-weighted image. No uterine structure or cervix found in between the bladder (red arrow) and the rectum. Coronal and axial MRI T2-weighted images show symmetrical masses within pelvis with lower density than subcutaneous fat on T2-weighted images. The images are consistent with cryptorchid testes and agenesis of the uterus seen in CAIS.

Photos courtesy of: Stephanie L. Lee

In these patients, because the Y chromosome expresses several genes such as AMH, SOX9 and SRY, testes develop normally and produce testosterone. The presence of AMH prevents the development of the Müllerian structures including the fallopian tubes, uterus and upper vagina. In CAIS, neither testosterone, which is required to maintain the Wolffian structures, nor DHT, which is metabolized by 5 alpha reductase from testosterone, can activate the AR to stimulate external masculinization. Therefore, the vas deferens, seminal vesicles and epididymis degenerate, the development of the penis and scrotum do not occur, the distal end of the vagina is either absent or shortened, ending in a blind pouch and sexual hair (chest, axillary and pubic) fail to grow. The testes will not descend and will remain either in the abdomen or inguinal region.

The testes in CAIS patients can be difficult to identify radiographically as they are small in size and can be anywhere within the abdomen, pelvis or inguinal region. In a small case series, MRI imaging of CAIS patients were analyzed retrospectively and showed that if the undescended testes were located, they were small and hypointense on T2-weighted scans compared with testes in the scrotum. MR can delineate whether that is agenesis or hypogenesis of the uterus but also the locations of the undescended testes. It is important to scan with thin slices caudally from the pelvis through the lower end of the inguinal canal with T2-weighted images. Ovaries appear different radiographically. Commonly, they appear cystic, especially in premenopausal women. Although the reported appearance of the ovaries on T2-weighted imaging is conflicting, the ovaries have been described as being iso-, hypo- and hyperintense when compared with surrounding tissue.

The frequency of malignant degeneration of the testes in CAIS patients is difficult to assess because of the small size of case series and sampling bias. Nonetheless, the patient was referred to urology and underwent a bilateral gonadectomy without complications. The pathology revealed testicular parenchyma with small seminiferous tubules without lamina composed of Sertoli cells only, focal Leydig cell hyperplasia and Wolffian/Müllerian duct cysts. No malignancy was seen. Weeks after her gonadectomy, the patient developed intolerable hot flashes, sweats and irritability. She was started on conjugated estrogens 0.625 mg daily with resolution of her symptoms. Her raloxifene therapy was discontinued after the diagnosis of CAIS was made and she was started on alendronate sodium 70 mg weekly; her next bone density showed a significant improvement in her T-score at the lumbar spine.

Beth M. Kaplan, MD, is a Fellow in Endocrinology and Stephanie L. Lee, MD, PhD, is Associate Chief, both in the Section of Endocrinology, Diabetes and Nutrition at Boston Medical Center.

For more information:

Jorgensen PB. Fertil Steril. 2009;doi:10.1016/j.fertstert. 2009.02.087.

McPhaul MJ. J Clin Endocrinol Metab. 1993;76:17-23.

Sobel V. J Clin Endocrinol Metab. 2006;91:3017-3023.

Tanaka YO. J Comput Assist Tomagr. 1998;22:884-888.