Dilemmas in management of osteoporosis in patients with complete androgen insensitivity syndrome

  1. Tanner Slayden 1,
  2. Elizabeth M Bauer 2,
  3. Mohamed KM Shakir 2 , 3 and
  4. Thanh Duc Hoang 2 , 3
  1. 1 Department of Internal Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
  2. 2 Department of Endocrinology, Diabetes & Metabolism, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
  3. 3 Department of Medicine, Uniformed Services University of the Health Sciences F Edward Hebert School of Medicine, Bethesda, Maryland, USA
  1. Correspondence to Dr Thanh Duc Hoang; tdhdthanh@gmail.com

Publication history

Accepted:20 Apr 2021
First published:12 May 2021
Online issue publication:12 May 2021

Case reports

Case reports are not necessarily evidence-based in the same way that the other content on BMJ Best Practice is. They should not be relied on to guide clinical practice. Please check the date of publication.

Abstract

Complete androgen insensitivity syndrome (CAIS)—resulting in 46,XY karyotype, but female phenotype—is a disorder of sex development and primary amenorrhea, but its effect on bone mineral density (BMD) is singular and difficult to manage. Androgens are an important modulator of bone remodeling and health, and the androgen receptor (AR) is pivotal for signaling within the bone cells. CAIS results in a severely disrupted AR throughout the body, causing an elevated risk of early osteoporosis. Timing of gonadectomy and hormone replacement therapy protocols are not established, creating a wide variety of treatment plans and BMD profiles. Our objective is to report a patient with CAIS status post prepubertal orchiectomy that developed early osteoporosis and to describe the lack of optimal strategies and consensus available to improve bone health in this population. Additionally, our case illustrates the fact there are no guidelines advocating the use of newer drugs for osteoporosis in this population.

Background

Complete androgen insensitivity syndrome (CAIS) due to loss-of-function mutation in the coding sequence of the androgen receptors (ARs) is a genetic disorder that has a novel effect on bone mineral density (BMD). The syndrome is an amalgamation of a variety of mutations on the AR resulting in a completely compromised response to endogenous and exogenous androgens.1 The hormone resistance results from defects in AR function. These patients with CAIS may have no detectable AR binding, decreased amounts of qualitatively normal receptor binding or qualitatively abnormal AR binding.2 The treatment and monitoring of this syndrome is complicated, but CAIS is a valuable model to assess androgen and oestrogen effects on bone health and the consequences of a total absence of androgen action.

It is difficult to generalise the time courses and effects of this syndrome on the skeletal system because of various treatment regimens and interventions used in these patients over the last several years. Additionally, because of the relative increased risk of gonadal malignancy and lack of established guidelines, patients may undergo prepubertal gonadectomy, postpubertal gonadectomy or maintain their gonads with routine monitoring. It is not well recognised that the timing of gonadectomy may affect bone health. There are also varying routes and doses of hormone replacement therapy (HRT) separate from the gonadectomy issue.

Case presentation

A 44-year-old phenotypic woman with a history of CAIS status post bilateral orchiectomy at the age of 4 years presented for endocrine follow-up. Her CAIS diagnosis was presumptively made following the physical evaluation (inguinal masses containing testes and absence of uterus), 46,XY karyotype and histological confirmation of the resected testes. She was previously on conjugated oestrogens tablets, Premarin, at various doses from the age of 12 years until her early 30s when her therapy became sporadic secondary to frequent changes of jobs. In 2014, she was prescribed topical oestrogen therapy, but discontinued soon after because of skin irritation. She had not been on any form of HRT since that time. The physical examination was significant for normal vital signs, a height of 75 inches, weight of 244 lbs, body mass index of 30.5, and no hirsutism, sparse axillary and pubic hair, Tanner 5 breasts, normal cardiopulmonary/abdominal/neurological examination. She had completely female external genitalia, but a short vagina. Pelvic CT scan confirmed the absence of uterus and ovaries.

Pertinent laboratory results are summarised in table 1.

Table 1

Relevant laboratory review

Laboratory test name Patient’s result Laboratory test reference
Estradiol 12.3 pg/mL 12.4–233 pg/mL
Total testosterone 12.0 ng/dL 7–40 ng/dL
Free testosterone 1.6 pg/dL 0.0–4.2 pg/dL
Androstenedione 48 ng/dL 41–262 ng/dL
Dihydrotestosterone 2.7 ng/dL 4–22 ng/dL
Dehydroepiandrosterone sulfate 209 ng/dL 31–701 ng/dL
Sex hormone binding globulin 62.8 nmol/L 11–110 nmol/L
Follicle stimulating hormone 109.6 mIU/mL 25.8–134.8 mIU/mL
Luteinising hormone 42.49 mIU/mL 7.7–58.5 mIU/mL
Anti-mullerian hormone <0.015 ng/mL 0.26–5.81
Inhibin B <7.0 pg/mL <17 pg/mL
Haemoglobin A1C 5.3%
25-hydroxy vitamin D 21.7 ng/mL 29–100 ng/mL
Serum calcium 9.7 mg/dL 8.6–10.2 mg/dL
Thyrotropin 2.68 µIU/mL 0.27–4.2 µIU/mL
Erythrocyte sedimentation rate 16 mm/hour 4–27 mm/hour
C reactive protein 0.472 mg/dL 0.0–0.5 mg/dL
Insulin-like growth factor -1 99 ng/mL 62–204 ng/mL
Comprehensive metabolic panel Unremarkable (ALP 85 U/L) ALP 35–104 U/L
Complete blood count Unremarkable
Urinalysis panel Unremarkable

  • The laboratory values were obtained after 10 hours of overnight fasting.

  • ALP, alkaline phosphatase.

Investigations

Karyotype was determined via cytogenetic analysis of phytohemagglutinin-stimulated cultures by Integrated Genetics (LabCorp Specialty Testing Group, Westborough, MA, USA). This test performed in adulthood confirmed non-mosaic karyotype of 46,XY (figure 1). Pertinent laboratory tests performed either at Walter Reed clinical laboratory or Lab Corps (Burlington, NC, USA; table 1) confirmed values consistent with postorchiectomy in our patient. A baseline dual-energy X-ray absorptiometry (DEXA) scan (Hologic) revealed T-scores of −2.0 lumbar-spine, −1.6 femoral neck, −1.1 total hip, −2.5 forearm and −3.5 whole body (figure 2). Of note, her Z-scores were −2.0 forearm and −3.1 whole body. Her 10-year fracture risk was 2.9% for major osteoporotic fracture and 0.3% for hip fracture using Fracture Risk Assessment Tool (FRAX) calculator.

Figure 1

Chromosome analysis showing a non-mosaic karyotype of 46,XY.

Figure 2

DEXA scan showing osteoporosis. DEXA, dual-energy X-ray absorptiometry.

Differential diagnosis

The differential diagnoses of CAIS include disorders of androgen biosynthesis or Leydig cell dysfunction, mullerian agenesis, mixed gonadal dysgenesis, etc. The differentials of partial androgen insensitivity syndrome may be extensive given the variable genotypic and phenotypic presentations. However, in our patient, the typical phenotypic features (completely normal female external genitalia and short vagina), histological confirmation of the resected testes, pelvic CT scan showing the absence of uterus and ovaries and the chromosome analysis confirmed CAIS. Majority of these patients with CAIS have missense mutations, while splicing abnormalities, premature termination codons, partial deletions and complete deletion of the AR gene can be found in the remaining patients.3 However, our patient did not consent for a genetic analysis due to the potential impacts on her military career.

Our patient had been evaluated for secondary causes of osteoporosis such as glucocorticoid use, alcoholism, malabsorption, and connective tissue disorders; and all these were negative.

Treatment

After being diagnosed with early osteoporosis via the WHO’s criteria (T-score: ≤−2.5),4 she was treated with estradiol 1 mg oral tablet two times per day.

The treatment of osteoporosis consists of lifestyle measures and pharmacologic therapy. The medications include antiresorptive agents such as bisphosphonates, denosumab, anabolic agents (teriparatide and abaloparatide) or romosozumab (antisclerostin). Other drugs used to treat osteoporosis include selective oestrogen receptor modulators, that is, raloxifene and bazedoxifene. Currently many Food and Drug Administration (FDA)-approved medications may not be used long-term (teriparatide and bisphosphonates) or may have adverse effects if used for a long time (atypical fractures, osteonecrosis of the jaw, etc). Although oestrogen-progestin therapy is no longer a first-line treatment for osteoporosis in postmenopausal women, this therapy may be beneficial in younger women.

At present, there is no guideline for the treatment of osteoporosis, especially in younger population with CAIS. After lengthy discussions, our patient was interested in estradiol therapy along with lifestyle measures.

Outcome and follow-up

Patient tolerates estradiol well without adverse effects and reports no recent falls or fractures. Patient continues a healthy lifestyle. Repeat DEXA scan 1 year later showed improvement of BMD in forearm and stability of lumbar spine and total hip BMD. The plan is to continue estradiol, calcium/vitamin D along with healthy lifestyle measures and continue monitoring BMD with DEXA scans. In the future, around 50 years of age, other treatments such as antiresorptive or anabolic therapies may be considered for her osteoporosis.

Discussion

Prophylactic gonadectomy has been recommended in CAIS because of an increased risk for development of malignant germ cell tumours in the intra-abdominal gonads, especially since no reliable screening methods are available to detect premalignant changes. Based on this early information, our patient underwent bilateral orchiectomy at the age of 4 years in 1976. Timing for gonadectomy has gone from one extreme to the other over recent years. Gonadectomy around the average age of 15 years reflected the standard practice in the 1970s. However, in the 1980s, the practice shifted away from removing the gonads during infancy for girls in whom an early diagnosis was made.1 Currently, gonadectomy is controversial as testicular tumours in CAIS have a low prevalence of malignancy than originally thought. Gonadectomy can subject patients to lifelong hormone replacement2 and potential detriments to their bone health. Bilateral inguinal hernias during childhood are no longer an absolute indication for prepubertal gonadectomy.5 The justification for delaying gonadectomy is that testicular malignancies develop at the usual rate for cryptorchid testes and seldom occurs before puberty.6 In fact, there has been no tumours reported in patients aged younger than 14 years.7 This supports delayed gonadectomy and reserving prepubertal surgery for only extreme cases. This will likely help at least some patients to avoid early osteoporosis as well as prevent the need of HRT to initiate puberty and sustain feminisation.

Decreased BMD in patients with CAIS following gonadectomy has been widely reported in the literature, with one recent review citing nine published studies supporting this claim.5 The reduction in BMD appears to be worse in the lumbar spine,8 suggesting a particularly important role for androgens on trabecular bone.9 Of note, oestrogen therapy typically improves BMD at the lumbar spine and hip in patients with CAIS after orchiectomy as these patients otherwise lack testosterone from the testes that can go through peripheral aromatisation and act on skeletal system via the oestrogen receptor alpha and/or beta.7 10 Androgens have also been shown to have a direct stimulatory effect on the oestrogen receptor located on osteoblasts.11 Orchiectomy in rodents caused high turnover bone loss, and postorchiectomy bone loss was prevented by treatment with both testosterone and dihydrotestosterone; in androgen receptor knockout mice, trabecular bone volume was diminished, presenting as high bone turnover osteoporosis.12 These data largely established a detrimental link between prepubertal gonadectomy in patients with CAIS as well as delaying HRT.

However, not all studies support these sequelae of postgonadectomy in patients with CAIS. In contrast, one study showed only modest improvements in vertebral DEXA values after 2 years of compliant HRT use. There was no correlation between hip or spine BMD with age of gonadectomy, age of starting HRT or duration of oestrogen deficiency.11 Another study supported these findings and was actually able to measure BMD before and after gonadectomy in 12 patients.7 It may be suggested that CAIS-associated normal DEXA values could be substantially different from the general female population, as patients with CAIS are taller.5 But it could also signify that androgen’s role in bone mineralisation is most pronounced in early life, before gonadectomy, or inadequate HRT doses were attained.

BMD studies in patients with CAIS after orchiectomy, especially in prepubertal age are limited (table 2).13–20 Only a limited number of patients have been studied and in these, lumbar BMDs were low although forearm BMD data were not included. There are only few studies examining longitudinal BMD in patients who have undergone prepubertal orchiectomy, especially since this was the preferred surgical procedure previously. Generally, in these patients, lumbar BMDs are more affected than femoral21, and this was also seen in our patient. HRT was also inconsistently used in these studies, and when it was used, varying dosages, formulations and frequencies were prescribed. Finally, very few of the studies included patients that went through prepubertal orchiectomies, which was interesting considering the historical prevalence of this practice. In a recent review from Bertelloni’s group, their results were comparable to our results and showed lumbar BMD being more affected than femoral.21

Table 2

Bone mineral density in patients with complete androgen insensitivity syndrome after orchiectomy

References N Prepuberty orchiectomy, % Age range, years Average Lumbar BMD Average Femoral Neck BMD Fractures
Soule et al 13 6 50 13–38 Low* Low* 1/6
Muñoz-Torres et al 14 1 0 17 Low† Low‡ n/a
Vered et al 15 1 0 39 Low‡ Low‡ n/a
Mizunuma et al 10 2 0 19–28 Low† Low† n/a
Bertelloni et al 16 10 20 4–20 Low‡ Not performed 0/10
Marcus et al 1 22 18 11–65 Normal†§ Normal† 6/22¶
Sobel et al 9 12 0 17–62 Low† Normal† n/a
Danilovic et al 17 8 0 20–25 Normal† Normal† 0/5
Han et al 11 46 26** 22–43 Low* Normal* n/a
Taes et al 18 1 0 31 Low† Normal† 1/1
Chin et al 19 1 0 14 Normal† Normal† n/a
King et al 7 113 0 35–40 Low* Normal* n/a
Gava et al 20 32 50** 24–45 Low* Low* 0/32

  • *Average T-scores provided for each study, unless specified otherwise: normal ≥−1.0 and low ≤−1.1.

  • †No T-score data available, so average Z-score used: normal ≥−1.9 and low ≤−2.0.

  • ‡No T-score or Z-score data: normal and low determined by authors’ determination.

  • §Noncompliance with oestrogen replacement therapy resulted in ‘low’ average BMD values.

  • ¶Three of the six patients reported multiple fractures.

  • **Difficult to extrapolate accurately based on the information from reference.

A major risk factor for fractures is decreased BMD and osteoporosis. But fracture risk in CAIS with or without gonadectomy has not been established, as also documented in table 2. Only two studies suggested an increased fracture risk in patients with CAIS postgonadectomy, but they were very low powered with no apparent fragility fractures. In the most dramatic study, six patients with CAIS sustained cortical bone fractures, and three reported multiple fractures1; in the other study, one patient sustained multiple pathologic fractures.13 Patients with CAIS have decreased BMD, which likely put them at a high risk for osteoporosis and fractures; but it is interesting that this had not been reflected substantially in the previous study populations.

In our patient, despite a lengthy period of oestrogen therapy, she still developed early osteoporosis. Our patient had no other risk factors for osteoporosis such as alcoholism and glucocorticoid therapy. The early osteoporosis is likely multifactorial with her primary diagnosis, prepubertal gonadectomy and prolonged HRT holiday playing a role. She also has a follicle stimulating hormone level in the postmenopausal range and this may have resulted from the low estradiol levels which possibly had an effect on osteoclasts,2 and in her bone health.

Currently, there are no guidelines on how to manage osteoporosis in this patient population. Evidence shows orchiectomy should be postponed until after puberty, but HRT protocols and the significance of low T-scores and Z-scores are not established.

Table 2 showing literature review of BMD (arranged in a chronological order from 1995 to 2019) in patients with CAIS after orchiectomy.

Learning points

  • Complete androgen insensitivity syndrome (CAIS) is often associated with an increased risk of osteoporosis in early adulthood secondary to a loss of function mutation in the androgen receptor.

  • To date, limited information has been published on CAIS’s hormonal milieu effects on the bone, and it is still not clear how clinicians can minimise osteoporosis-related fractures in these patients as conventional hormone replacement therapy and dosing have only modest results.

  • At present, there are no guidelines regarding the management of patients with CAIS who had already undergone prepubertal gonadectomy.

  • Certainly, by establishing early intervention criteria to optimise bone mineral density in patients with CAIS, we can prevent disease progress and improve quality of life.

Acknowledgments

The authors created their own tables 1 and 2.

Footnotes

  • Twitter @tdhdthanh

  • Contributors TS and EMB: reviewed the manuscript. MKMS and TDH: reviewed and edited the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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