The Intraovarian Sites of Androgen and Estrogen Formation in Women with Normal and Hyperandrogenic Ovaries as Judged by<i>in Vitro</i>Experiments*

McNatty, Kenneth P.; Smith, Deborah Deutsch; Makris, Anastasia; Degrazia, Camillo; Tulchinsky, Dan; Osathanondh, Rapin; Schiff, Isaac; Ryan, Kenneth J.

doi:10.1210/jcem-50-4-755

Cited by 72 publications

(20 citation statements)

References 12 publications

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“…In PCOS follicles, the low follicular fluid oestradiol concentrations were not different from size matched follicles in regularly cycling control women. These results are in agreement with previous studies that also found similar oestradiol concentrations (McNatty et al, 1980;Pache et al, 1992;Mason et al, 1994). Our findings are also in agreement with the only study to address the endogenous aromatase activity of granulosa cells in PCOS (Erickson et al, 1979).…”

Section: Discussionsupporting

confidence: 94%

Aromatase mRNA expression in individual follicles from polycystic ovaries

Jakimiuk¹

1998

Molecular Human Reproduction

109

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Polycystic ovary syndrome (PCOS) is a common reproductive disorder characterized by arrested follicular development prior to selection of a dominant follicle. Dominant follicles produce large amounts of oestradiol but PCOS follicles do not. With several potential aromatase (P450 AROM ) inhibitors in follicular fluid, the question arises whether P450 AROM is expressed in PCOS granulosa cells, but the activity is inhibited, or whether P450 AROM is not expressed in PCOS. The purpose of the present study was to determine whether P450 AROM mRNA expression is altered in PCOS and to correlate P450 AROM mRNA expression in individual follicles with aromatase stimulatory bioactivity and oestradiol in the follicular microenvironments. P450 AROM mRNA was measured in individual follicles from 16 PCOS and 48 regularly cycling control women by quantitative polymerase chain reaction (PCR) and correlated with follicular fluid oestradiol concentrations and aromatase stimulating bioactivity measured by the rat granulosa cells aromatase bioassay. Follicular fluid oestradiol was low in all control follicles <7 mm in diameter. Some follicles ജ7 mm contained elevated oestradiol values (P < 0.01) and all had an androstenedione:oestradiol ratio of Ͻ4. Only in granulosa cells from follicles ജ7 mm with an androstenedione:oestradiol ratio of <4 were P450 AROM mRNA levels increased (P < 0.05). These same follicles also contained increased levels of aromatase stimulating bioactivity whereas follicles <7 mm or with androstenedione:oestradiol ratio of >4 contained little or no bioactivity. All PCOS follicles contained low levels of oestradiol , P450 AROM mRNA and aromatase stimulating bioactivity similar to size-matched control follicles. These data indicate that P450 AROM mRNA expression and oestradiol production begin in developing follicles when they reach~7 mm in diameter. Oestradiol production is low in PCOS follicles because there is insufficient aromatase stimulating bioactivity to increase P450 AROM mRNA expression.

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Section: Discussionsupporting

confidence: 94%

Aromatase mRNA expression in individual follicles from polycystic ovaries

Jakimiuk¹

1998

Molecular Human Reproduction

109

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“…Considering the fact that the action of high concentrations of insulin can be mediated via IGF-I receptors and that IGF-I receptor expression is increased in the thecal stromal cells of PCO ovaries despite the remarkable decrease in insulin receptors, it is possible that hyperinsulinemia in PCO patients may intensify androgen production by thecal stromal cells by reacting with IGF-I receptors. This possibility is further supported by the observation of McNatty et al [38] that ovarian stromal tissues of a patient with insulin-resistant diabetes produced 50-to 250-fold more androgen than did the ovarian stromal tissues from normal women. Taken together, as suggested by Barbieri et al [6,39], it is likely that one of the common disorders in PCO might be insulin resistance, with a consequent increase in insulin levels, which in turn stimulates ovarian thecal stromal androgen production.…”

Section: Discussionmentioning

confidence: 78%

Altered Expression of Insulin and Insulin-Like Growth Factor-l Receptors in Follicular and Stromal Compartments of Polycystic Ovaries.

et al. 1993

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Abstract. In the ovary, insulin and insulin-like growth factor-I (IGF-I) act synergistically with FSH to augment estrogen production by granulosa cells and with LH to augment androgen production by thecal stromal cells. It is also evident that insulin resistance is common in patients with polycystic ovary syndrome (PCO). Thus, in the present study we investigated the expression of insulin and IGF-I receptors in PCO ovaries and compared them with those in normal ovaries. Ovarian tissues were obtained from four PCO patients undergoing wedge resection, and from six patients who underwent radical hysterectomy. Immunohistochemical staining for insulin and IGF-I receptors was performed by avidin/biotin immunoperoxidase techniques. In normal ovaries, the expression of insulin and IGF-I receptors in follicular compartment became apparent in the preantral follicle stage and augmented with the follicular growth, while the stromal cells, regardless of the follicle stage, possessed insulin and IGF-I receptors. In PCO ovaries associated with hyperinsulinemia, no expression of insulin receptors was detected in granulosa or thecal stromal cells, while IGF-I receptor expression increased in thecal stromal cells but decreased in granulosa cells compared to those in normal ovaries. However, in PCO ovaries from patients without hyperinsulinemia, insulin receptor expression was apparent in both granulosa and thecal stromal cells, with a similar intensity to that observed in normal ovaries, while IGF-I receptor expression was negligible in granulosa cells but sustained in thecal stromal cells. These findings suggest that decreased expression of insulin receptors in PCO ovaries associated with hyperinsulinemia may be secondary to receptor down regulation, whereas defective expression in granulosa cells along with elevated or persisted expression in thecal stromal cells of IGF-I receptors may be common in PCO ovaries and contribute to the endocrine profiles of PCO in which varying degrees of hyperandrogenism is a predominant feature.

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“…Investigations in 1993 showed fasting blood sugar (FBS) level of 5.7 mmol/L, follicle stimulating hormone (FSH) 11 IU/L (normal [3][4][5][6][7][8][9][10][11][12], luteinizing hormone (LH) 11 IU/L (normal 0. [5][6][7][8][9][10][11], and prolactin (PRL) 415 mIU/L (normal 55-450).…”

Section: Resultsmentioning

confidence: 99%

“…[5][6][7][8][9][10][11], and prolactin (PRL) 415 mIU/L (normal 55-450). Oral glucose tolerance test (OGTT) showed a diabetic curve, while growth hormone (GH) was normal throughout the study.…”

Section: Resultsmentioning

confidence: 99%

“…2 Macnatty et al have found that the ovaries are the site of androgen production. 9 Kahn, Bar and colleagues found a marked decrease in the insulin receptors on the white blood cells of some patients with the HAIR-AN syndrome (type A insulin resistance), and in a patient with the HAIR-AN syndrome and Kahn type-c insulin resistance the insulin receptors themselves appeared to be normal and post-receptor defects in insulin action were postulated. 4,10 So the HAIR component of the HAIR-AN syndrome is very common, the AN being an epiphenomenon of the hyperandrogenism and hyperinsulinemia.…”

Section: Discussionmentioning

confidence: 99%

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The Hair-An Syndrome: A Report of a Misdiagnosed Case with Unfortunate Outcome

Fouda

1998

Ann Saudi Med

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The HAIR-AN syndrome, which consists of hyperandrogenism (HA), insulin resistance (IR) and acanthosis nigricans (AN), is an underdiagnosed endocrinopathy.2 Hyperandrogenic women are seen frequently in clinical practice, the challenge being to identify a cause and source of the problem. Many such patients are classified, after thorough investigations, as polycystic ovary syndrome (PCOS). The problem with this identification is that the PCOS encompasses a wide range of clinical and laboratory presentations and, therefore, classification into subgroups may help in understanding the process and thereby targeting the management in a more appropriate way. 2The HAIR-AN syndrome is an example of a unique entity with a specific molecular basis. It was thought to be a rare syndrome, but recent experience suggests that as many as 5% of hyperandrogenic women have this syndrome. 3Here we report a classical case of HAIR-AN which had an unfortunate outcome because of initial misdiagnosis. Case ReportA 20-year-old girl presented to the Endocrinology clinic with a history of being healthy until the age of 11 years, when she started experiencing right iliac fossa pain, followed by progressive change in voice, increased body and facial hair, increased pigmentation of skin, increased sweating, with heat intolerance and persistent bitemporal headache. She also noticed enlargement of hands and feet in the six years before presentation, prompting her to change shoes and watches frequently. For the previous three years, she had been experiencing polyuria and polydipsia, was told to have diabetes mellitus, and put on a diet. She had primary amenorrhea, and was put on a combination of pills which resulted in oligomenorrhea with dysmenorrhoea. She later stopped the medication.In 1990, the patient had been seen in another hospital, had been diagnosed with appendicitis, and appendectomy was performed to remove a mass found in the right iliac fossa (there was no report on the nature of the mass). In 1993, an ultrasound scan revealed a well-defined solid mass in the pelvis, suggestive of a left ovarian tumor, and the right ovary was visualized. The ovarian mass was subsequently excised. A frozen section done at the time was inconclusive. Paraffin sections did, however, show histological features consistent with a right polycystic ovary and mild hyperthecosis (Figure 1).Upon presentation to the Endocrine clinic, examination of the patient revealed a depressed girl who was not very communicative. She was about 162 cm tall, weighed 62.2 kg and had a BP of 140/80. She had a large face with big nose and macroglossia. Her hands and feet were large and bulky, with mainly soft tissue enlargement and nonpitting edema of the lower limbs. She had significant facial hirsutism with hypertrichosis over the rest of the body and coarse terminal hair over the limbs.Acanthosis nigricans was positive at the flexor surfaces, neck, axillae, cubital fossae and the base of the neck. Abdominal examination revealed the scars of the previous two operations, with no or...

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The Intraovarian Sites of Androgen and Estrogen Formation in Women with Normal and Hyperandrogenic Ovaries as Judged byin VitroExperiments*

Cited by 72 publications

References 12 publications

Aromatase mRNA expression in individual follicles from polycystic ovaries

Aromatase mRNA expression in individual follicles from polycystic ovaries

Altered Expression of Insulin and Insulin-Like Growth Factor-l Receptors in Follicular and Stromal Compartments of Polycystic Ovaries.

The Hair-An Syndrome: A Report of a Misdiagnosed Case with Unfortunate Outcome

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