Table 4.
Biochemical response to gonadotrophin-releasing hormone analogues in primary severe insulin resistance
| Patient | Clinical & genetic diagnosis | Clinical presentation | Agea, y | Before treatment | After treatment | Ref | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Insulin, pmol/L | TT, ng/dL | LH, U/L | FSH, U/L | GnRH analogue | Timeb | TT, ng/dL | LH, U/L | FSH, U/L | |||||
| P10 |
Insulin resistance with diabetes
TBC1D4 13:75324235 A>C splice site donor heterozygous (rs201722427) |
Hair growth on chin, back, and chest age 12. Diabetes age 14, with worsening hirsutism, cystic acne (face and chest) and clitoromegaly (clitoral length 4 cm, index 42 mm2, normal <35 mm2). No improvement after metformin. 22.5 mg intramuscular leuprolide acetate administered age 15, after which testosterone levels decreased. No change in HbA1c after 6 months (insulin was not measured). Lost to follow up. | 15 | 1051 | 334 | 3.6 | 2.9 | Leuprorelin | 16 days | 100 | 2.3 | 1.7 | |
| P11 |
Rabson–Mendenhall syndrome
INSR p.Ile146Met homozygous (rs121913159) |
At age 16 with primary amenorrhea, clitoromegaly and facial hirsutism requiring shaving. Ferriman–Gallwey score 14, Tanner III breast development, Tanner IV pubic hair, clitoral index 105 mm2 (normal <35mm2). Multiple small ovarian follicles but no large cysts on pelvic ultrasound. 11.25mg leuprorelin acetate depot injections initiated 8-weekly with COCP. Reduction in testosterone and clitoral index over 4 months, without reported changes in mood, libido or shaving frequency. Insulin sensitivity did not change. | 16 | 1320 | 980 | 11.6 | 8.8 | Leuprorelin | 4 months | 60 | 1.2 | 2.1 | |
| P4c |
Type A insulin resistance
INSR p.Phe409Val homozygous (rs121913142) |
See Table 2 for history prior to oophorectomy. Persistent virilization, hirsutism, and amenorrhea aged 23 (4 years post unilateral oophorectomy). Daily subcutaneous injections of leuprolide initiated. Serum testosterone improved but remained elevated. Underwent completion oophorectomy 5 years after GnRH initiation. | 23 | NA | 912 | 27.5 | 10.4 | Leuprorelin | 1 year | 73–267 | NA | NA | A5 in (22) |
| P12 | Type B insulin resistance | At aged 29 with secondary amenorrhea and symptomatic diabetes due to INSR autoantibodies. Lean with prominent hirsutism and acne. Bilateral bulky ovaries, stromal hyperplasia and proliferating immature follicles on MRI. Leuprorelin commenced; testosterone reduced by 75% after 2 months, insulin requirements remained high. Systemic lupus erythematosus diagnosed. Immunosuppressive therapy initiated with rapid improvement in glycemic control. Serum testosterone concentration normal after 24 months. | 30 | 4749 | 1562 | 4 | 2 | Leuprorelin | 2 months | 432 | NA | NA | |
| P13 | Type B insulin resistance | At age 29 with hyperinsulinemia and testosterone in the adult male range with INSR autoantibodies. Spontaneous remission of autoantibody with resolution of hyperandrogenemia. Autoantibody recurred 2 years later, manifesting as hyperglycemia, worsening acanthosis, voice changes, and increased shaving. Treatment with leuprorelin led to normalization of serum testosterone, despite persistent extreme insulin resistance, with decreased frequency of shaving, improved acne, softer voice, and better mood. | 32 | 1715 | 778 | 7.8 | 5.5 | Leuprorelin | 2 months | 33.7 | 0.4 | 1.8 | (30) |
| P14 | Acquired partial lipodystrophy (in childhood) with juvenile dermatomyositis | Diagnosed with PCOS in 30s (hirsutism and oligomenorrhoea), treated with cyproterone acetate. Hirsutism returned after cyproterone discontinued at age 51. MRI showed single ovarian cysts bilaterally (22mm and 19mm diameter). Medical comorbidities precluded oophorectomy therefore goserelin commenced (3.6 mg monthly). Facial hirsutism improved and testosterone levels normalized after 3 months. After 6 months, goserelin stopped, hirsutism returned, and serum testosterone concentration rose above normal. Goserelin restarted, and testosterone remained suppressed after 18 months. | 53 | 300 | 444 | 21 | 35.2 | Goserelin | 3 months | 14.4 | 4.8 | 19.3 | |
Abbreviations: COCP, combination oral contraceptive pill. FSH, follicle-stimulating hormone; INSR, insulin receptor; LH, luteinizing hormone; TT, total testosterone. N/A: data unavailable.
a Age at start of therapy.
b Time (in specified units) since onset of GnRH analogue therapy at re-evaluation.
c Also reported in Table 3. Insulin was measured in the fasting state.