Table 3.
Ovarian pathology associated with primary severe insulin resistance
| Patient | Clinical and genetic diagnosis | Clinical presentation | Agea, years | Insulinb, pmol/L | TTb, ng/dL | Ovarian pathology | Ref. |
|---|---|---|---|---|---|---|---|
| P1 |
Donohue syndrome
INSR p.Cys264Tyr/p.Thr488Pro (compound heterozygous) |
In infancy with abdominal distention and respiratory distress. Also growth retardation, lipoatrophy, acanthosis nigricans, hirsutism, hypertrichosis, and clitoromegaly. Bilateral oophorectomy due to respiratory distress. Received recombinant human IGF1. | 0.33 | 19446 | 127 | Massive bilateral ovarian enlargement (left 103 g, right 230 g). Multiple follicular cysts with stromal hyperthecosis, consistent with PCOS (Fig 4A-C). | (20) |
| P2 |
Digenic insulin resistance with partial lipodystrophy
PPARG (A469ΔAAAiT) fs.156(stop 157) / PPP1R3A (C1984ΔAG) fs.662(stop 668) digenic heterozygous (rs587776687, rs527638422) |
Post-puberty with an abdominal mass associated with hirsutism, secondary amenorrhea, acanthosis nigricans. Large bilateral fallopian and ovarian cysts on pelvic ultrasound, prompting unilateral oophorectomy. Postoperatively, hirsutism responded to combination cyproterone acetate and ethinylestradiol. | 14 | 276 | N/A | Abdominal mass due to large fallopian and ovarian cysts. Multiple follicular cysts with stromal hyperthecosis, consistent with PCOS.(25) | (21, 29) |
| P3 |
Insulin resistance with diabetes
AKT2 p.Arg274His heterozygous (rs121434593) |
At age 16 with secondary amenorrhea, hirsutism, acne, virilization, prompting bilateral ovarian wedge resection. Regular menses thereafter, and 2 successful pregnancies. At age 35 with acromegaloid facies and hands. Diabetes aged 38 with worsening hirsutism, necrobiosis lipoidica and high insulin requirements. Total abdominal hysterectomy and left salpingo-oophorectomy aged 42 for menorrhagia. At age 50 with large right sided pelvic mass with hydronephrosis, liver and pulmonary nodules. Presumed metastatic epithelial ovarian cancer. Died 7 days later. |
16 | N/A | N/A | Ovarian wedge resection age 16 consistent with PCOS. Uterine fibroid age 42. Presumed epithelial ovarian cancer age 50. |
Mother of proband in (17) |
| P4c |
Type A insulin resistance with diabetes
INSR p.Phe409Val homozygous (rs121913142) |
At age 8 with hirsutism. Menarche aged 12. At age 15, persistent hyperandrogenemia with polycystic ovarian morphology on pelvic ultrasound, prompting bilateral wedge resection. Left ovarian oophorectomy aged 19. Later GnRH analogue therapy (see Table 4). | 19 | N/A | >1000 | Left ovary 2.43mL (excluding cyst). Numerous follicular cysts, stroma extensively luteinized with islands of thecal cells, consistent with PCOS. 9 × 9 × 8cm ovarian cystadenoma. | A5 in (22) |
| P5 |
Rabson-Mendenhall syndrome
INSR p.Pro220Leu homozygous (rs749094324) |
Treated from age 8 with leptin, high-dose insulin (900 units/day) and metformin. At age 19, amenorrheic with extensive hirsutism, hyperandrogenemia and bilaterally enlarged multicystic ovaries on pelvic ultrasound. Bilateral oophorectomy for hyperandrogenism. Testosterone undetectable after 8 months. | 19 | 3688 | 648 | Bilateral ovarian enlargement (left 60.5 mL, right 23.2 mL). Histology consistent with PCOS. Within this, a serous cystadenoma was identified. | RM-PaL in (23), female patient in (24), RMS-2 in (25) |
| P6 |
Type A insulin resistance with diabetes
INSR p.Trp160*/p.Asn489Ser compound heterozygous (rs121913146, rs1135401742) |
Insulin resistant diabetes from age 12 (>30,000 units/day). Menarche at age 15 with irregular menses thereafter. Hirsutism from age 23, clitoral index 150 mm2 (normal <35 mm2). Bilateral oophorectomy for massively enlarged ovaries and hyperandrogenism. Testosterone normalized after 3 months. | 23 | N/A | 935 | Bilateral ovarian enlargement (left 50 mL, right 36 mL). Numerous small dark cysts in both ovaries with abundant dense ovarian stroma, consistent with PCOS. | A1 in 4, 22, 26 |
| P7 |
Familial partial lipodystrophy with diabetes
Unknown genetic etiology |
In early 20s with secondary amenorrhea, truncal and facial hirsutism, acne, acanthosis nigricans and hyperandrogenemia. Heterogeneous left ovarian mass on CT, bilateral oophorectomy age 27. Postoperatively, testosterone concentrations normalized, hirsutism persisted, no change in metabolic status. | 27 | 212 | 332 | Left ovary: numerous follicular cysts, stromal hyperthecosis, resembling PCOS. Within this, a steroid cell tumor was identified (Fig 4D-H) | - |
| P8 |
Familial partial lipodystrophy with diabetes
PPARG p.Pro467Leu heterozygous (rs121909244) |
In teens with generalized hirsutism and irregular menses after menarche aged 11. At age 17, ovarian biopsy consistent with PCOS. At age 28, COCP normalized menses and slowed hair growth for 6 months, and testosterone was undetectable. Hyperandrogenism recurred after discontinuation of therapy. Bilateral oophorectomy at age 29, following which testosterone undetectable. | 29 | 2778 | N/A | Histology consistent with PCOS. | A7 in (22) |
| P9 |
Familial partial lipodystrophy with diabetes
PPARG p.Pro467Leu heterozygous (rs121909244) |
Oligomenorrhoea and menorrhagia in 20s and 30s. Atypical polypoid hyperplasia within an endometrial polyp prompted total abdominal hysterectomy age 45. Presented age 48 with hirsutism, temporal alopecia, increased muscle bulk, voice change, acanthosis nigricans. Hyperandrogenemia with a left ovarian tumor. Symptoms regressed and testosterone normalized after bilateral salpingo-oophorectomy. | 48 | N/A | 1240 | 144mL left ovary containing moderately differentiated Sertoli-Leydig cell tumor (Meyer’s type 2). | (27) |
Abbreviations: COCP, combination oral contraceptive pill; TT, total testosterone; PCOS, polycystic ovary syndrome. N/A: data unavailable.
a Age corresponding to ovarian histology.
b Measured prior to oophorectomy or ovarian biopsy. Insulin was measured in the fasting state.
c Also reported in Table 4. Normal ovarian volume 5 mL.