**2.1. Recognition of insulin resistance in CAH**

The first report of insulin resistance in CAH was published by Speiser et al. in female patients with non-classic 21-hydroxylase deficiency [1].

In 1994 Andersson et al. reported that women with type 2 Diabetes Mellitus (T2DM), the archetypal insulin-resistant condition, had higher mean free testosterone levels, higher waist/ hip ratios, lower sex hormone-binding globulin (SHBG) levels, and higher plasma insulin levels than gender/BMI matched controls [2]. In commenting on the report of Andersson et al., Sacerdote reported a sample of 57 consecutive male and female T2DMs, all of whom had adrenal hyperandrogenism [3].

In 2005 Saygili et al. reported that women with non-classic 21-hydroxylase deficiency were both insulin and leptin resistant compared BMI-matched controls [4].

Several groups have reported insulin resistance as a common feature of both classic 21 hydroxylase deficiency and classic 11-hydroxylase activity [5-14]. Importantly, in most of these studies, the insulin resistance was independent of the corticosteroid dosage, suggesting that it is intrinsic to CAH, rather than a result of exogenous corticosteroid. Glucocorticoid receptor polymorphism (BcII GR variant) may contribute to the insulin resistance as reported by Moreira et al [14].

In 2006 we reported additional endocrine disrupter effects of two classes of drugs used in antiretroviral therapy that were already known to cause insulin resistance, protease inhibitors and nucleoside analogues-the induction/unmasking of adrenal hyperplasia [15].

Despite the slowly growing recognition that insulin resistance is an intrinsic feature of both CAH and acquired/unmasked CAH, just at is in PCOS, the medical community has been very slow in exploring treatment approaches based on improving insulin sensitivity analogous to the treatment approaches now used so successfully in PCOS. This is despite the widely recognized limitations of mainstream corticosteroid replacement therapy, which, as excellent as it is, often cannot normalize androgen levels without producing adverse effects of glucocorticoid excess, such as decreased bone mineral density, hyperglycemia, soft-tissue changes, and affective changes. The respective advantages and disadvantages of corticosteroid replacement therapy, including the latest advances are discussed extensive‐ ly in our earlier chapter [16].

## **2.2. Treating CAH by reducing insulin resistance**

**•** The induction of PCOS and enhanced 1-α-hydroxylation of 25-OH-vitamin D by parasite

The first report of insulin resistance in CAH was published by Speiser et al. in female patients

In 1994 Andersson et al. reported that women with type 2 Diabetes Mellitus (T2DM), the archetypal insulin-resistant condition, had higher mean free testosterone levels, higher waist/ hip ratios, lower sex hormone-binding globulin (SHBG) levels, and higher plasma insulin levels than gender/BMI matched controls [2]. In commenting on the report of Andersson et al., Sacerdote reported a sample of 57 consecutive male and female T2DMs, all of whom had

In 2005 Saygili et al. reported that women with non-classic 21-hydroxylase deficiency were

Several groups have reported insulin resistance as a common feature of both classic 21 hydroxylase deficiency and classic 11-hydroxylase activity [5-14]. Importantly, in most of these studies, the insulin resistance was independent of the corticosteroid dosage, suggesting that it is intrinsic to CAH, rather than a result of exogenous corticosteroid. Glucocorticoid receptor polymorphism (BcII GR variant) may contribute to the insulin resistance as reported by

In 2006 we reported additional endocrine disrupter effects of two classes of drugs used in antiretroviral therapy that were already known to cause insulin resistance, protease inhibitors and

Despite the slowly growing recognition that insulin resistance is an intrinsic feature of both CAH and acquired/unmasked CAH, just at is in PCOS, the medical community has been very slow in exploring treatment approaches based on improving insulin sensitivity analogous to the treatment approaches now used so successfully in PCOS. This is despite the widely recognized limitations of mainstream corticosteroid replacement therapy, which, as excellent as it is, often cannot normalize androgen levels without producing adverse effects of glucocorticoid excess, such as decreased bone mineral density, hyperglycemia, soft-tissue changes, and affective changes. The respective advantages and disadvantages of corticosteroid replacement therapy, including the latest advances are discussed extensive‐

**•** The amelioration of the latter by alteration of the hormonal milieu.

both insulin and leptin resistant compared BMI-matched controls [4].

nucleoside analogues-the induction/unmasking of adrenal hyperplasia [15].

endocrine disruption.

104 Contemporary Gynecologic Practice

**2. Insulin resistance in CAH**

adrenal hyperandrogenism [3].

Moreira et al [14].

ly in our earlier chapter [16].

**2.1. Recognition of insulin resistance in CAH**

with non-classic 21-hydroxylase deficiency [1].

In 2000 we reported the first series of patients with T2DM/pre-diabetes and non-classic CAH (NCAH) in whom the biochemical and clinical features of NCAH were ameliorated by treatment with metformin and/or troglitazone [17], from 2 different classes of insulin sensi‐ tizers, biguanides and thiazolidinediones.

In 2003 we reported that the biochemical/phenotypic expression of NCAH, including 21 hydroxylase deficiency, 3-β-ol dehydrogenase deficiency, 11-hydroxylase deficiency, and aldosterone synthase deficiency could be ameliorated with the thiazolidinedione insulin sensitizer, rosiglitazone [18]. An example of this is shown in Figure 1. Of note, in this patient, the observed sharp drop in serum 17-OH-progesterone occurred within 24 hours of initiating rosiglitazone, consistent with an effect on DNA transcription/ mRNA translation. In 2003 we reported that the biochemical/phenotypic expression of NCAH, including 21-hydroxylase deficiency, 3-β-ol dehydrogenase deficiency, 11-hydroxylase deficiency, and aldosterone synthase deficiency could be ameliorated with the thiazolidinedione insulin sensitizer, rosiglitazone (18). An example of this is shown in Figure 1. Of note, in this patient, the observed sharp drop in serum 17-OHprogesterone occurred within 24 hours of initiating rosiglitazone, consistent with an effect on DNA transcription/ mRNA translation. In 2003 we reported that the biochemical/phenotypic expression of NCAH, including 21-hydroxylase deficiency, 3-β-ol dehydrogenase deficiency, 11-hydroxylase deficiency, and aldosterone synthase deficiency could be ameliorated with the thiazolidinedione insulin sensitizer, rosiglitazone (18). An example of this is shown in Figure 1. Of note, in this patient, the observed sharp drop in serum 17-OHprogesterone occurred within 24 hours of initiating rosiglitazone, consistent with an effect on DNA transcription/ mRNA translation.

**Figure 1.** Response of a 43 year old male's 17-OH-Progesterone (ng/dl) to rosiglitazone 4mg bid.

**Figure 1.** Response of a 43 year old male's 17-OH-Progesterone (ng/dl) to rosiglitazone 4mg bid.

**Figure 1.** Response of a 43 year old male's 17-OH-Progesterone (ng/dl) to rosiglitazone 4mg bid.

In 2004 we reported that the biochemical/phenotypic expression of NCAH is ameliorated by pioglitazone (19). An example of the combined effect of metformin and pioglitazone compared with standard glucocorticoid/mineralocorticoid replacement therapy in a patient with non-classical 21-hydroxylase deficiency is shown in Figure 2. Note that the response of the patient's serum 17-OH-progesterone to the insulin sensitizers, metformin and pioglitazone is more complete than to the standard of care therapy with glucocorticoid and mineralocorticoid. In 2004 we reported that the biochemical/phenotypic expression of NCAH is ameliorated by pioglitazone [19]. An example of the combined effect of metformin and pioglitazone compared with standard glucocorticoid/mineralocorticoid replacement therapy in a patient with non-classical 21-hydroxylase deficiency is shown in Figure 2. Note that the response of the patient's serum 17-OH-progesterone to the insulin sensitizers, metformin and pioglitazone is more complete than to the standard of care therapy with glucocorticoid and mineralocorticoid. In 2004 we reported that the biochemical/phenotypic expression of NCAH is ameliorated by pioglitazone (19). An example of the combined effect of metformin and pioglitazone compared with standard glucocorticoid/mineralocorticoid replacement therapy in a patient with non-classical 21-hydroxylase deficiency is shown in Figure 2. Note that the response of the patient's serum 17-OH-progesterone to the insulin sensitizers, metformin and pioglitazone is more complete than to the standard of care therapy with glucocorticoid and mineralocorticoid.

**Figure 2.** Response of a 57 year old female's 17-OH-Progesterone (ng/dl) to cortisone acetate, metformin, & pioglitazone

**Figure 2.** Response of a 57 year old female's 17-OH-Progesterone (ng/dl) to cortisone acetate, metformin, & pioglitazone

Arslanian et al. reported that metformin therapy in obese teen-agers with PCOS and impaired glucose tolerance (IGT) attenuated the

Arslanian et al. reported that metformin therapy in obese teen-agers with PCOS and impaired glucose tolerance (IGT) attenuated the

In 2007 we reported that the anti-psychotic drugs and valproate, which were already known to cause insulin resistance and, in the case of the latter, PCOS, also induced and/or unmasked adrenal hyperplasia (21). This endocrine disrupter effect of these drugs was reversible

In 2007 we reported that the anti-psychotic drugs and valproate, which were already known to cause insulin resistance and, in the case of the latter, PCOS, also induced and/or unmasked adrenal hyperplasia (21). This endocrine disrupter effect of these drugs was reversible

> 17 OH Preg = 17-OH-pregnenolone 17-OH Progest = 17-OH-progesterone

17 OH Preg = 17-OH-pregnenolone 17-OH Progest = 17-OH-progesterone

DOC = deoxycorticosterone 11 DOC = 11-deoxycortisol E1 = estrone, E2 = estradiol

DOC = deoxycorticosterone 11 DOC = 11-deoxycortisol E1 = estrone, E2 = estradiol

**Figure 2.** Response of a 57 year old female's 17-OH-Progesterone (ng/dl) to cortisone acetate, metformin, & pioglita‐ zone

with the insulin sensitizers metformin (Figure 3) or rosiglitazone (Figure 4).

with the insulin sensitizers metformin (Figure 3) or rosiglitazone (Figure 4).

**0**

**4200**

**androstenedione**

**androstenedione**

**17OH Preg.**

**17OH Preg.**

**DOC**

**DOC**

**E1/E2 Reversed**

**E1/E2 Reversed**

**11-DOC**

**11-DOC**

**17-OH Progest.**

**17-OH Progest.**

**E1/E2**

**E1/E2**

**17-oh Preg.**

**17-oh Preg.**

exaggerated adrenocortical response to ACTH with a reduction in hyperinsulinemia/insulin resistance (20)..

exaggerated adrenocortical response to ACTH with a reduction in hyperinsulinemia/insulin resistance (20)..

**Figure 3.** Effect of metformin on elevated steroid metabolites in 8 patients (represented as % of baseline)

**Figure 3.** Effect of metformin on elevated steroid metabolites in 8 patients (represented as % of baseline)

2

mineralocorticoid.

Arslanian et al. reported that metformin therapy in obese teen-agers with PCOS and impaired glucose tolerance (IGT) attenuated the exaggerated adrenocortical response to ACTH with a reduction in hyperinsulinemia/insulin resistance [20].. Arslanian et al. reported that metformin therapy in obese teen-agers with PCOS and impaired glucose tolerance (IGT) attenuated the

**Figure 1.** Response of a 43 year old male's 17-OH-Progesterone (ng/dl) to rosiglitazone 4mg bid.

In 2007 we reported that the anti-psychotic drugs and valproate, which were already known to cause insulin resistance and, in the case of the latter, PCOS, also induced and/or unmasked adrenal hyperplasia [21]. This endocrine disrupter effect of these drugs was reversible with the insulin sensitizers metformin (Figure 3) or rosiglitazone (Figure 4). exaggerated adrenocortical response to ACTH with a reduction in hyperinsulinemia/insulin resistance (20).. In 2007 we reported that the anti-psychotic drugs and valproate, which were already known to cause insulin resistance and, in the case of the latter, PCOS, also induced and/or unmasked adrenal hyperplasia (21). This endocrine disrupter effect of these drugs was reversible with the insulin sensitizers metformin (Figure 3) or rosiglitazone (Figure 4).

**Figure 3.** Effect of metformin on elevated steroid metabolites in 8 patients (represented as % of baseline)

17 OH Preg = 17-OH-pregnenolone 17-OH Progest = 17-OH-progesterone DOC = deoxycorticosterone 11 DOC = 11-deoxycortisol E1 = estrone, E2 = estradiol

**Figure 4**. Effect of rosiglitazone on elevated baseline 11-Deoxycortisol level (mg/dl) in 2 patients

results shown here and declined further dose titration and/or addition of other insulin sensitizers.

addition of metformin to standard corticosteroid therapy (Figures 5,6) (22). The patient was a 17 year old woman, whose CAH had been diagnosed in the nursery, where she had become profoundly dehydrated, whose current complaints were of amenorrhea, hirsutism, and acne, despite being adherent to optimal glucocorticoid/mineralocorticoid therapy. As can be seen in figure 5, her baseline serum 17-OHprogesterone on standard therapy was still very elevated, while her baseline serum total testosterone (Figure 6) was actually in the lower reference range for adult males. While maintaining this therapy, metformin 500 mg twice daily after meals was added. Co-incident with the marked reduction in both her serum 17-OH-progesterone and serum testosterone levels documented at her next visit, she noted the return of monthly menses, the absence of new acne lesions, and a reduction in hirsutism. While we would have liked to continue to titrate her metformin dose upward to 2 grams daily and, if necessary, added a second insulin-sensitizing agent in an attempt to normalize her steroid metabolite levels, and then possibly, wean her off corticosteroids altogether, the patient pronounced herself pleased with the

**Figure 5.** Effect of metformin on 17-OH-progesterone (ng/dl) in a patient with classical, salt-wasting 21-Hydroxylase deficiency

metformin 500 mg twice daily

baseline

**Figure 6.** Effect of metformin on serum total testosterone (ng/dl) in classical, salt-wasting 21-Hydroxylase deficiency

baseline

the latter two forms, which are exceptionally well-tolerated, are often not covered by prescription insurance.

Before proceeding to discuss other insulin-sensitizing options in the treatment of CAH and endocrine-disrupter induced/unmasked adrenal hyperplasia, it is worth discussing a few limitations to their use. Despite their demonstrated efficacy, these insulin sensitizers have still not been demonstrated to be able to totally replace corticosteroids in classical CAH nor have they been prescribed, to our knowledge, in

metformin 500 mg twice daily

The main limitation of metformin use is gastrointestinal intolerance. Much of this problem may be overcome by prescribing more gastrointestinal-friendly forms of metformin such as extended release, liquid (Riomet), or matrix-embedded (Glumetza). Unfortunately,

 Another significant limitation of metformin use is that is inappropriate to use in patients with seriously compromised renal function due to an increased risk of lactic acidosis. In the U.S. it is recommended that metformin not be used in women with serum creatinine >1.4 mg/dl or men with serum creatinine > 1.5 mg/dl. In several other countries guidelines are allowing its use at lower doses down to an

The use of thiazolidinediones is limited because there is little experience with this class of drugs in mid-late pregnancy and there is

Another means of improving insulin sensitivity is with diet and exercise. This approach was utilized in 2 patients with non-classic aldosterone synthase deficiency (Figure 7) (23). Diet and exercise resulted in a 10% weight reduction accompanied by a normalization of

In 2003 we reported that the biochemical/phenotypic expression of NCAH, including 21-hydroxylase deficiency, 3-β-ol dehydrogenase deficiency, 11-hydroxylase deficiency, and aldosterone synthase deficiency could be ameliorated with the thiazolidinedione insulin sensitizer, rosiglitazone (18). An example of this is shown in Figure 1. Of note, in this patient, the observed sharp drop in serum 17-OHprogesterone occurred within 24 hours of initiating rosiglitazone, consistent with an effect on DNA transcription/ mRNA translation.

rosiglitazone 4 mg twice daily

baseline

In 2004 we reported that the biochemical/phenotypic expression of NCAH is ameliorated by pioglitazone (19). An example of the combined effect of metformin and pioglitazone compared with standard glucocorticoid/mineralocorticoid replacement therapy in a patient with non-classical 21-hydroxylase deficiency is shown in Figure 2. Note that the response of the patient's serum 17-OH-progesterone to the insulin sensitizers, metformin and pioglitazone is more complete than to the standard of care therapy with glucocorticoid and

metformin and pioglitazone

**Figure 2.** Response of a 57 year old female's 17-OH-Progesterone (ng/dl) to cortisone acetate, metformin, & pioglitazone

baseline cortisone metformin

2

3

**Figure 3.** Effect of metformin on elevated steroid metabolites in 8 patients (represented as % of baseline)

In 2008 we published the first report of a patient with classical, salt losing 21-hydroxylase deficiency being successfully treated with the **Figure 4.** Effect of rosiglitazone on elevated baseline 11-Deoxycortisol level (mg/dl) in 2 patients

forms of CAH such as lipoid CAH.

concern about weight gain, bone loss, and bladder cancer.

eGFR > 35 ml/min.

baseline

**Figure 5.** Effect of metformin on 17-OH-progesterone (ng/dl) in a patient with classical, salt-wasting 21-Hydroxylase deficiency

steroid metabolite levels, and then possibly, wean her off corticosteroids altogether, the patient pronounced herself pleased with the

baseline

**Figure 6.** Effect of metformin on serum total testosterone (ng/dl) in classical, salt-wasting 21-Hydroxylase deficiency

been demonstrated to be able to totally replace corticosteroids in classical CAH nor have they been prescribed, to our knowledge, in

The main limitation of metformin use is gastrointestinal intolerance. Much of this problem may be overcome by prescribing more gastrointestinal-friendly forms of metformin such as extended release, liquid (Riomet), or matrix-embedded (Glumetza). Unfortunately,

been demonstrated to be able to totally replace corticosteroids in classical CAH nor have they been prescribed, to our knowledge, in

 Another significant limitation of metformin use is that is inappropriate to use in patients with seriously compromised renal function due to an increased risk of lactic acidosis. In the U.S. it is recommended that metformin not be used in women with serum creatinine >1.4 mg/dl or men with serum creatinine > 1.5 mg/dl. In several other countries guidelines are allowing its use at lower doses down to an

The main limitation of metformin use is gastrointestinal intolerance. Much of this problem may be overcome by prescribing more gastrointestinal-friendly forms of metformin such as extended release, liquid (Riomet), or matrix-embedded (Glumetza). Unfortunately,

The use of thiazolidinediones is limited because there is little experience with this class of drugs in mid-late pregnancy and there is

 Another significant limitation of metformin use is that is inappropriate to use in patients with seriously compromised renal function due to an increased risk of lactic acidosis. In the U.S. it is recommended that metformin not be used in women with serum creatinine >1.4 mg/dl or men with serum creatinine > 1.5 mg/dl. In several other countries guidelines are allowing its use at lower doses down to an

Another means of improving insulin sensitivity is with diet and exercise. This approach was utilized in 2 patients with non-classic aldosterone synthase deficiency (Figure 7) (23). Diet and exercise resulted in a 10% weight reduction accompanied by a normalization of

The use of thiazolidinediones is limited because there is little experience with this class of drugs in mid-late pregnancy and there is

Another means of improving insulin sensitivity is with diet and exercise. This approach was utilized in 2 patients with non-classic aldosterone synthase deficiency (Figure 7) (23). Diet and exercise resulted in a 10% weight reduction accompanied by a normalization of

Arslanian et al. reported that metformin therapy in obese teen-agers with PCOS and impaired glucose tolerance (IGT) attenuated the In 2007 we reported that the anti-psychotic drugs and valproate, which were already known to cause insulin resistance and, in the case of the latter, PCOS, also induced and/or unmasked adrenal hyperplasia (21). This endocrine disrupter effect of these drugs was reversible In 2008 we published the first report of a patient with classical, salt losing 21-hydroxylase deficiency being successfully treated with the addition of metformin to standard corticosteroid therapy (Figures 5,6) [22]. The patient was a 17 year old woman, whose CAH had been diagnosed in the nursery, where she had become profoundly dehydrated, whose current complaints were of amenorrhea, hirsutism, and acne, despite being adherent to optimal glucocorticoid/mineralocorticoid therapy. As can be seen in figure 5, her baseline serum 17- OH-progesterone on standard therapy was still very elevated, while her baseline serum total testosterone (Figure 6) was actually in the lower reference range for adult males. While maintaining this therapy, metformin 500 mg twice daily after meals was added. Co-incident with the marked reduction in both her serum 17-OH-progesterone and serum testosterone levels documented at her next visit, she noted the return of monthly menses, the absence of new acne lesions, and a reduction in hirsutism. While we would have liked to continue to titrate her metformin dose upward to 2 grams daily and, if necessary, added a second insulinsensitizing agent in an attempt to normalize her steroid metabolite levels, and then possibly, wean her off corticosteroids altogether, the patient pronounced herself pleased with the results shown here and declined further dose titration and/or addition of other insulin sensitizers. In 2008 we published the first report of a patient with classical, salt losing 21-hydroxylase deficiency being successfully treated with the addition of metformin to standard corticosteroid therapy (Figures 5,6) (22). The patient was a 17 year old woman, whose CAH had been diagnosed in the nursery, where she had become profoundly dehydrated, whose current complaints were of amenorrhea, hirsutism, and acne, despite being adherent to optimal glucocorticoid/mineralocorticoid therapy. As can be seen in figure 5, her baseline serum 17-OHprogesterone on standard therapy was still very elevated, while her baseline serum total testosterone (Figure 6) was actually in the lower reference range for adult males. While maintaining this therapy, metformin 500 mg twice daily after meals was added. Co-incident with the marked reduction in both her serum 17-OH-progesterone and serum testosterone levels documented at her next visit, she noted the return of monthly menses, the absence of new acne lesions, and a reduction in hirsutism. While we would have liked to continue to titrate her metformin dose upward to 2 grams daily and, if necessary, added a second insulin-sensitizing agent in an attempt to normalize her steroid metabolite levels, and then possibly, wean her off corticosteroids altogether, the patient pronounced herself pleased with the results shown here and declined further dose titration and/or addition of other insulin sensitizers. **0 40 80 patient 1 patient 2** In 2008 we published the first report of a patient with classical, salt losing 21-hydroxylase deficiency being successfully treated with the addition of metformin to standard corticosteroid therapy (Figures 5,6) (22). The patient was a 17 year old woman, whose CAH had been diagnosed in the nursery, where she had become profoundly dehydrated, whose current complaints were of amenorrhea, hirsutism, and acne, despite being adherent to optimal glucocorticoid/mineralocorticoid therapy. As can be seen in figure 5, her baseline serum 17-OHprogesterone on standard therapy was still very elevated, while her baseline serum total testosterone (Figure 6) was actually in the lower reference range for adult males. While maintaining this therapy, metformin 500 mg twice daily after meals was added. Co-incident with the marked reduction in both her serum 17-OH-progesterone and serum testosterone levels documented at her next visit, she noted the return of monthly menses, the absence of new acne lesions, and a reduction in hirsutism. While we would have liked to continue to titrate her metformin dose upward to 2 grams daily and, if necessary, added a second insulin-sensitizing agent in an attempt to normalize her **0 40 80 120 160 patient 1 patient 2**

**Figure 4**. Effect of rosiglitazone on elevated baseline 11-Deoxycortisol level (mg/dl) in 2 patients

**Figure 4**. Effect of rosiglitazone on elevated baseline 11-Deoxycortisol level (mg/dl) in 2 patients

Arslanian et al. reported that metformin therapy in obese teen-agers with PCOS and impaired glucose tolerance (IGT) attenuated the exaggerated adrenocortical response to ACTH with a

**Figure 1.** Response of a 43 year old male's 17-OH-Progesterone (ng/dl) to rosiglitazone 4mg bid.

In 2003 we reported that the biochemical/phenotypic expression of NCAH, including 21-hydroxylase deficiency, 3-β-ol dehydrogenase deficiency, 11-hydroxylase deficiency, and aldosterone synthase deficiency could be ameliorated with the thiazolidinedione insulin sensitizer, rosiglitazone (18). An example of this is shown in Figure 1. Of note, in this patient, the observed sharp drop in serum 17-OHprogesterone occurred within 24 hours of initiating rosiglitazone, consistent with an effect on DNA transcription/ mRNA translation.

rosiglitazone 4 mg twice daily

baseline

In 2004 we reported that the biochemical/phenotypic expression of NCAH is ameliorated by pioglitazone (19). An example of the combined effect of metformin and pioglitazone compared with standard glucocorticoid/mineralocorticoid replacement therapy in a patient with non-classical 21-hydroxylase deficiency is shown in Figure 2. Note that the response of the patient's serum 17-OH-progesterone to the insulin sensitizers, metformin and pioglitazone is more complete than to the standard of care therapy with glucocorticoid and

metformin and pioglitazone

17 OH Preg = 17-OH-pregnenolone 17-OH Progest = 17-OH-progesterone

baseline

rosiglitazone

addition of metformin to standard corticosteroid therapy (Figures 5,6) (22). The patient was a 17 year old woman, whose CAH had been diagnosed in the nursery, where she had become profoundly dehydrated, whose current complaints were of amenorrhea, hirsutism, and acne, despite being adherent to optimal glucocorticoid/mineralocorticoid therapy. As can be seen in figure 5, her baseline serum 17-OHprogesterone on standard therapy was still very elevated, while her baseline serum total testosterone (Figure 6) was actually in the lower reference range for adult males. While maintaining this therapy, metformin 500 mg twice daily after meals was added. Co-incident with the marked reduction in both her serum 17-OH-progesterone and serum testosterone levels documented at her next visit, she noted the return of monthly menses, the absence of new acne lesions, and a reduction in hirsutism. While we would have liked to continue to titrate her metformin dose upward to 2 grams daily and, if necessary, added a second insulin-sensitizing agent in an attempt to normalize her steroid metabolite levels, and then possibly, wean her off corticosteroids altogether, the patient pronounced herself pleased with the

eGFR > 35 ml/min.

eGFR > 35 ml/min.

forms of CAH such as lipoid CAH.

**300 350**

**200 240**

**Figure 5.** Effect of metformin on 17-OH-progesterone (ng/dl) in a patient with classical, salt-wasting 21-Hydroxylase deficiency

metformin 500 mg twice daily

baseline

**Figure 6.** Effect of metformin on serum total testosterone (ng/dl) in classical, salt-wasting 21-Hydroxylase deficiency

baseline

the latter two forms, which are exceptionally well-tolerated, are often not covered by prescription insurance.

Before proceeding to discuss other insulin-sensitizing options in the treatment of CAH and endocrine-disrupter induced/unmasked adrenal hyperplasia, it is worth discussing a few limitations to their use. Despite their demonstrated efficacy, these insulin sensitizers have still not been demonstrated to be able to totally replace corticosteroids in classical CAH nor have they been prescribed, to our knowledge, in

metformin 500 mg twice daily

The main limitation of metformin use is gastrointestinal intolerance. Much of this problem may be overcome by prescribing more gastrointestinal-friendly forms of metformin such as extended release, liquid (Riomet), or matrix-embedded (Glumetza). Unfortunately,

 Another significant limitation of metformin use is that is inappropriate to use in patients with seriously compromised renal function due to an increased risk of lactic acidosis. In the U.S. it is recommended that metformin not be used in women with serum creatinine >1.4 mg/dl or men with serum creatinine > 1.5 mg/dl. In several other countries guidelines are allowing its use at lower doses down to an

The use of thiazolidinediones is limited because there is little experience with this class of drugs in mid-late pregnancy and there is

Another means of improving insulin sensitivity is with diet and exercise. This approach was utilized in 2 patients with non-classic aldosterone synthase deficiency (Figure 7) (23). Diet and exercise resulted in a 10% weight reduction accompanied by a normalization of

DOC = deoxycorticosterone 11 DOC = 11-deoxycortisol E1 = estrone, E2 = estradiol

results shown here and declined further dose titration and/or addition of other insulin sensitizers.

**Figure 2.** Response of a 57 year old female's 17-OH-Progesterone (ng/dl) to cortisone acetate, metformin, & pioglitazone

baseline cortisone metformin

In 2007 we reported that the anti-psychotic drugs and valproate, which were already known to cause insulin resistance and, in the case of the latter, PCOS, also induced and/or unmasked adrenal hyperplasia [21]. This endocrine disrupter effect of these drugs was reversible with

exaggerated adrenocortical response to ACTH with a reduction in hyperinsulinemia/insulin resistance (20)..

**Figure 3.** Effect of metformin on elevated steroid metabolites in 8 patients (represented as % of baseline)

reduction in hyperinsulinemia/insulin resistance [20]..

mineralocorticoid.

106 Contemporary Gynecologic Practice

**0**

**40**

**80**

**120**

**160**

**200**

**240**

**androstenedione**

**17OH Preg.**

**DOC**

forms of CAH such as lipoid CAH.

concern about weight gain, bone loss, and bladder cancer.

eGFR > 35 ml/min.

**E1/E2 Reversed**

**patient 1 patient 2**

**11-DOC**

**17-OH Progest.**

**Figure 4.** Effect of rosiglitazone on elevated baseline 11-Deoxycortisol level (mg/dl) in 2 patients

**E1/E2**

**Figure 3.** Effect of metformin on elevated steroid metabolites in 8 patients (represented as % of baseline)

**17-oh Preg.**

the insulin sensitizers metformin (Figure 3) or rosiglitazone (Figure 4).

with the insulin sensitizers metformin (Figure 3) or rosiglitazone (Figure 4).

2 **Figure 6.** Effect of metformin on serum total testosterone (ng/dl) in classical, salt-wasting 21-Hydroxylase deficiency **Figure 5.** Effect of metformin on 17-OH-progesterone (ng/dl) in a patient with classical, salt-wasting 21-Hydroxylase deficiency **0 500**

In 2008 we published the first report of a patient with classical, salt losing 21-hydroxylase deficiency being successfully treated with the forms of CAH such as lipoid CAH. Before proceeding to discuss other insulin-sensitizing options in the treatment of CAH and endocrine-disrupter induced/unmasked adrenal hyperplasia, it is worth discussing a few limitations to their use. Despite their demonstrated efficacy, these insulin sensitizers have still not **Figure 6.** Effect of metformin on serum total testosterone (ng/dl) in classical, salt-wasting 21-Hydroxylase deficiency

concern about weight gain, bone loss, and bladder cancer.

concern about weight gain, bone loss, and bladder cancer.

the latter two forms, which are exceptionally well-tolerated, are often not covered by prescription insurance.

the latter two forms, which are exceptionally well-tolerated, are often not covered by prescription insurance.

3

3

.

insulin sensitizer (27).

Before proceeding to discuss other insulin-sensitizing options in the treatment of CAH and endocrine-disrupter induced/unmasked adrenal hyperplasia, it is worth discussing a few limitations to their use. Despite their demonstrated efficacy, these insulin sensitizers have still not been demonstrated to be able to totally replace corticosteroids in classical CAH nor have they been prescribed, to our knowledge, in forms of CAH such as lipoid CAH.

The main limitation of metformin use is gastrointestinal intolerance. Much of this problem may be overcome by prescribing more gastrointestinal-friendly forms of metformin such as extended release, liquid (Riomet), or matrix-embedded (Glumetza). Unfortunately, the latter two forms, which are exceptionally well-tolerated, are often not covered by prescription insurance.

Another significant limitation of metformin use is that is inappropriate to use in patients with seriously compromised renal function due to an increased risk of lactic acidosis. In the U.S. it is recommended that metformin not be used in women with serum creatinine >1.4 mg/dl or men with serum creatinine > 1.5 mg/dl. In several other countries guidelines are allowing its use at lower doses down to an eGFR > 35 ml/min.

The use of thiazolidinediones is limited because there is little experience with this class of drugs in mid-late pregnancy and there is concern about weight gain, bone loss, and bladder cancer.

Another means of improving insulin sensitivity is with diet and exercise. This approach was utilized in 2 patients with non-classic aldosterone synthase deficiency (Figure 7) [23]. Diet and exercise resulted in a 10% weight reduction accompanied by a normalization of the elevated serum deoxycorticosterone levels and normalization of the elevated LH/FSH ratio and improvement in the clinical features of virilization. the elevated serum deoxycorticosterone levels and normalization of the elevated LH/FSH ratio and improvement in the clinical features of virilization.

**Figure 7.** % Changes with weight loss &exercise in 2 women with non-classic aldosterone synthase deficiency

Metabolic or bariatric surgery in obese T2DM patients has been associated with an improvement in insulin sensitivity associated with

Ashwagandha root (*Withania somnifera*) has been used for millennia in Aryuvedic medicine, where it has proven effective in treating a number of specific conditions as well as being used as a general "tonic". We recently reported a patient who complained of excessive scalp hair shedding who was investigated and found to have both non-classic 3-β-ol-dehydrogenase deficiency and aldosterone synthase deficiency with elevated baseline levels of both serum 17-OH-pregnenolone and corticosterone (26). The patient had been able to reduce her rate of scalp hair loss and normalized her serum levels of both steroid metabolites while taking pioglitazone 15 mg/day. The patient elected to, nevertheless, stop pioglitazone because of what she had read on the internet concerning osteoporosis and bladder carcinoma. She promptly started losing excessive scalp hair again. After watching the Dr. Oz television program she decided to start a standardized preparation of Ashwagandha root 400 mg twice daily as a general 'tonic" and anti-oxidant. At her next visit she reported that she was awakening in the morning with much less hair on her pillow. Repeat serum levels of 17-OH-pregnenolone and corticosterone again fell to normal while using Ashwagandha root (Figures 9,10). A report by Anwer et al. confirms that Ashwagandha, among other effects, is an

metformin + pioglitazone 500 mg

post Roux-en-Y gastric bypass

baseline

twice daily

weight loss, suppression of inappropriate glucagon secretion via observed increases in GLP-1, reductions in glucose toxicity via improved **Figure 7.** Changes with weight loss &exercise in 2 women with non-classic aldosterone synthase deficiency

glycemic control, and increased glucose utilization associated with intestinal villous hypertrophy/hyperplasia distal to the anastomotic site. It is also reported to ameliorate PCOS (24). We reported the first patient in whom Roux-en Y gastric bypass not only caused the patient's T2DM and hypertension to remit, but also normalized the biochemical and clinical expression of her non-classical 11 hydroxylase deficiency (Figure 8) (25). **Figure 8.** Response of patient's 11-Deoxycortisol (ng/dl), nl < 51 to Roux-en-Y gastric bypass Metabolic or bariatric surgery in obese T2DM patients has been associated with an improve‐ ment in insulin sensitivity associated with weight loss, suppression of inappropriate glucagon secretion via observed increases in GLP-1, reductions in glucose toxicity via improved glycemic control, and increased glucose utilization associated with intestinal villous hyper‐ trophy/hyperplasia distal to the anastomotic site. It is also reported to ameliorate PCOS [24].

**Figure 9.** Response of patient's serum 17-OH-Pregnenolone (ng/dl) to Ashwagandha 400 mg twice daily

baseline ashwaganda

glycemic control, and increased glucose utilization associated with intestinal villous hypertrophy/hyperplasia distal to the anastomotic

number of specific conditions as well as being used as a general "tonic". We recently reported a patient who complained of excessive

**Figure 9.** Response of patient's serum 17-OH-Pregnenolone (ng/dl) to Ashwagandha 400 mg twice daily

the elevated serum deoxycorticosterone levels and normalization of the elevated LH/FSH ratio and improvement in the clinical features of

**Figure 7.** % Changes with weight loss &exercise in 2 women with non-classic aldosterone synthase deficiency

the elevated serum deoxycorticosterone levels and normalization of the elevated LH/FSH ratio and improvement in the clinical features of

BMI = body mass index DOC = deoxycortisone LH = luteinizing hormone

Metabolic or bariatric surgery in obese T2DM patients has been associated with an improvement in insulin sensitivity associated with weight loss, suppression of inappropriate glucagon secretion via observed increases in GLP-1, reductions in glucose toxicity via improved glycemic control, and increased glucose utilization associated with intestinal villous hypertrophy/hyperplasia distal to the anastomotic

FSH = follicle stimulating hormone

BMI = body mass index DOC = deoxycortisone LH = luteinizing hormone FSH = follicle stimulating hormone

**Figure 7.** % Changes with weight loss &exercise in 2 women with non-classic aldosterone synthase deficiency

We reported the first patient in whom Roux-en Y gastric bypass not only caused the patient's T2DM and hypertension to remit, but also normalized the biochemical and clinical expression of her non-classical 11-hydroxylase deficiency (Figure 8) [25]. site. It is also reported to ameliorate PCOS (24). We reported the first patient in whom Roux-en Y gastric bypass not only caused the patient's T2DM and hypertension to remit, but also normalized the biochemical and clinical expression of her non-classical 11 hydroxylase deficiency (Figure 8) (25). . hydroxylase deficiency (Figure 8) (25). **Figure 8.** Response of patient's 11-Deoxycortisol (ng/dl), nl < 51 to Roux-en-Y gastric bypass

**Figure 8.** Response of patient's 11-Deoxycortisol (ng/dl), nl < 51 to Roux-en-Y gastric bypass

Ashwagandha root (*Withania somnifera*) has been used for millennia in Aryuvedic medicine, where it has proven effective in treating a **Figure 8.** Response of patient's 11-Deoxycortisol (ng/dl), nl < 51 to Roux-en-Y gastric bypass **0**

**weight BMI DOC LH/FSH**

**weight BMI DOC LH/FSH**

virilization.

virilization.

**0**

**20**

**40**

**60**

**80**

**100**

.

50 100

Before proceeding to discuss other insulin-sensitizing options in the treatment of CAH and endocrine-disrupter induced/unmasked adrenal hyperplasia, it is worth discussing a few limitations to their use. Despite their demonstrated efficacy, these insulin sensitizers have still not been demonstrated to be able to totally replace corticosteroids in classical CAH nor have

The main limitation of metformin use is gastrointestinal intolerance. Much of this problem may be overcome by prescribing more gastrointestinal-friendly forms of metformin such as extended release, liquid (Riomet), or matrix-embedded (Glumetza). Unfortunately, the latter two forms, which are exceptionally well-tolerated, are often not covered by prescription

Another significant limitation of metformin use is that is inappropriate to use in patients with seriously compromised renal function due to an increased risk of lactic acidosis. In the U.S. it is recommended that metformin not be used in women with serum creatinine >1.4 mg/dl or men with serum creatinine > 1.5 mg/dl. In several other countries guidelines are allowing its

The use of thiazolidinediones is limited because there is little experience with this class of drugs in mid-late pregnancy and there is concern about weight gain, bone loss, and bladder cancer. Another means of improving insulin sensitivity is with diet and exercise. This approach was utilized in 2 patients with non-classic aldosterone synthase deficiency (Figure 7) [23]. Diet and exercise resulted in a 10% weight reduction accompanied by a normalization of the elevated serum deoxycorticosterone levels and normalization of the elevated LH/FSH ratio and

**Figure 8.** Response of patient's 11-Deoxycortisol (ng/dl), nl < 51 to Roux-en-Y gastric bypass

Metabolic or bariatric surgery in obese T2DM patients has been associated with an improve‐ ment in insulin sensitivity associated with weight loss, suppression of inappropriate glucagon secretion via observed increases in GLP-1, reductions in glucose toxicity via improved glycemic control, and increased glucose utilization associated with intestinal villous hyper‐ trophy/hyperplasia distal to the anastomotic site. It is also reported to ameliorate PCOS [24].

**Figure 7.** Changes with weight loss &exercise in 2 women with non-classic aldosterone synthase deficiency

**Figure 9.** Response of patient's serum 17-OH-Pregnenolone (ng/dl) to Ashwagandha 400 mg twice daily

baseline ashwaganda

Ashwagandha root (*Withania somnifera*) has been used for millennia in Aryuvedic medicine, where it has proven effective in treating a number of specific conditions as well as being used as a general "tonic". We recently reported a patient who complained of excessive scalp hair shedding who was investigated and found to have both non-classic 3-β-ol-dehydrogenase deficiency and aldosterone synthase deficiency with elevated baseline levels of both serum 17-OH-pregnenolone and corticosterone (26). The patient had been able to reduce her rate of scalp hair loss and normalized her serum levels of both steroid metabolites while taking pioglitazone 15 mg/day. The patient elected to, nevertheless, stop pioglitazone because of what she had read on the internet concerning osteoporosis and bladder carcinoma. She promptly started losing excessive scalp hair again. After watching the Dr. Oz television program she decided to start a standardized preparation of Ashwagandha root 400 mg twice daily as a general 'tonic" and anti-oxidant. At her next visit she reported that she was awakening in the morning with much less hair on her pillow. Repeat serum levels of 17-OH-pregnenolone and corticosterone again fell to normal while using Ashwagandha root (Figures 9,10). A report by Anwer et al. confirms that Ashwagandha, among other effects, is an

metformin + pioglitazone 500 mg

post Roux-en-Y gastric bypass

baseline

twice daily

**Figure 7.** % Changes with weight loss &exercise in 2 women with non-classic aldosterone synthase deficiency

BMI = body mass index DOC = deoxycortisone LH = luteinizing hormone

FSH = follicle stimulating hormone

they been prescribed, to our knowledge, in forms of CAH such as lipoid CAH.

use at lower doses down to an eGFR > 35 ml/min.

improvement in the clinical features of virilization.

**weight BMI DOC LH/FSH**

hydroxylase deficiency (Figure 8) (25).

insulin sensitizer (27).

insurance.

108 Contemporary Gynecologic Practice

virilization.

**0**

**20**

**40 60**

**80**

**100**

.

the elevated serum deoxycorticosterone levels and normalization of the elevated LH/FSH ratio and improvement in the clinical features of scalp hair shedding who was investigated and found to have both non-classic 3-β-ol-dehydrogenase deficiency and aldosterone synthase deficiency with elevated baseline levels of both serum 17-OH-pregnenolone and corticosterone (26). The patient had been able to reduce her rate of scalp hair loss and normalized her serum levels of both steroid metabolites while taking pioglitazone 15 mg/day. The patient elected to, nevertheless, stop pioglitazone because of what she had read on the internet concerning osteoporosis and bladder carcinoma. She promptly started losing excessive scalp hair again. After watching the Dr. Oz television program she decided to start a standardized preparation of Ashwagandha root 400 mg twice daily as a general 'tonic" and anti-oxidant. At her next visit she reported that she was awakening in the morning with much less hair on her pillow. Repeat serum levels of 17-OH-pregnenolone and corticosterone again fell to normal while using Ashwagandha root (Figures 9,10). A report by Anwer et al. confirms that Ashwagandha, among other effects, is an insulin sensitizer (27). **Figure 9.** Response of patient's serum 17-OH-Pregnenolone (ng/dl) to Ashwagandha 400 mg twice daily 150 200 250 300 350 400 450 baseline ashwaganda Ashwagandha root (*Withania somnifera*) has been used for millennia in Aryuvedic medicine, where it has proven effective in treating a number of specific conditions as well as being used as a general "tonic". We recently reported a patient who complained of excessive scalp hair shedding who was investigated and found to have both non-classic 3-β-ol-dehydrogenase deficiency and aldosterone synthase deficiency with elevated baseline levels of both serum 17- OH-pregnenolone and corticosterone [26]. The patient had been able to reduce her rate of scalp hair loss and normalized her serum levels of both steroid metabolites while taking pioglitazone 15 mg/day. The patient elected to, nevertheless, stop pioglitazone because of what she had read on the internet concerning osteoporosis and bladder carcinoma. She promptly started losing excessive scalp hair again. After watching the Dr. Oz television program she decided to start a standardized preparation of Ashwagandha root 400 mg twice daily as a general 'tonic" and anti-oxidant. At her next visit she reported that she was awakening in the morning with much less hair on her pillow. Repeat serum levels of 17-OH-pregnenolone and cortico‐ sterone again fell to normal while using Ashwagandha root (Figures 9,10). A report by Anwer et al. confirms that Ashwagandha, among other effects, is an insulin sensitizer [27]. Ashwagandha root (*Withania somnifera*) has been used for millennia in Aryuvedic medicine, where it has proven effective in treating a number of specific conditions as well as being used as a general "tonic". We recently reported a patient who complained of excessive scalp hair shedding who was investigated and found to have both non-classic 3-β-ol-dehydrogenase deficiency and aldosterone synthase deficiency with elevated baseline levels of both serum 17-OH-pregnenolone and corticosterone (26). The patient had been able to reduce her rate of scalp hair loss and normalized her serum levels of both steroid metabolites while taking pioglitazone 15 mg/day. The patient elected to, nevertheless, stop pioglitazone because of what she had read on the internet concerning osteoporosis and bladder carcinoma. She promptly started losing excessive scalp hair again. After watching the Dr. Oz television program she decided to start a standardized preparation of Ashwagandha root 400 mg twice daily as a general 'tonic" and anti-oxidant. At her next visit she reported that she was awakening in the morning with much less hair on her pillow. Repeat serum levels of 17-OH-pregnenolone and corticosterone again fell to normal while using Ashwagandha root (Figures 9,10). A report by Anwer et al. confirms that Ashwagandha, among other effects, is an insulin sensitizer (27).

4

4

**Figure 9.** Response of patient's serum 17-OH-Pregnenolone (ng/dl) to Ashwagandha 400 mg twice daily

**500**

**Figure 10.** Response of patient's serum corticosterone (ng/dl) to Ashwagandha 400 mg Twice Daily

**Figure 11.** Changes in serum 11-deoxycortisol (left) as a function of changes in serum 25-OH-Vitamin D3 (right) at baseline and at 9

**Figure 11.** Changes in serum 11-deoxycortisol (left) as a function of changes in serum 25-OH-Vitamin D3 (right) at baseline and at 9

 Most recently, we have reported a patient whose non-classic 11-hydroxylase deficiency was improved by taking a combination of Vitamin D and the GLP-1 receptor agonist liraglutide (Figure 12) (31). GLP-1 receptor agonists improve insulin sensitivity by suppressing the inappropriate secretion of the counter-regulatory hormone, glucagon, decreasing glucose toxicity by lowering post-

**Figure 12.** Response of Patient's Serum 11-Deoxycortisol (ng/dl; ref. range <42 ng/dl) to treatment with ergocalciferol & liraglutide

suppressing the inappropriate secretion of the counter-regulatory hormone, glucagon, decreasing glucose toxicity by lowering post-

**Figure 12.** Response of Patient's Serum 11-Deoxycortisol (ng/dl; ref. range <42 ng/dl) to treatment with ergocalciferol & liraglutide

11/8/2012 8/6/2012 5/3/2012

11/8/2012

8/6/2012 5/3/2012

**C. Possible Mechanisms by Which Reducing Insulin Resistance Ameliorates Congenital Adrenal Hyperplasia** 

Kelly et al. studied the effects of insulin in an *in vitro* human adrenocortical cell culture (32). They reported that steroidogenic factor-1 (SF-1) activity is up-regulated in vitro by insulin in the presence of forskolin (a functional analog of ACTH in this setting). Increased SF-1 synthesis, as well as increased binding of SF-1 to its response element, resulted in increased transcription of CYP17 causing increased adrenal androgen synthesis in both normal, human adrenocortical tissue and in cultures of the adrenocortical tumor line H-295. In these same two *in vitro* systems insulin inhibited the forskolin (ACTH) stimulated synthesis of the transcription factor *nur77*, an action that results in decreased transcription of CYP21 mRNA, further directing adrenal steroidogenesis toward androgen vs cortisol biosynthesis.

**C. Possible Mechanisms by Which Reducing Insulin Resistance Ameliorates Congenital Adrenal Hyperplasia** 

Kelly et al. studied the effects of insulin in an *in vitro* human adrenocortical cell culture (32). They reported that steroidogenic factor-1 (SF-1) activity is up-regulated in vitro by insulin in the presence of forskolin (a functional analog of ACTH in this setting). Increased SF-1 synthesis, as well as increased binding of SF-1 to its response element, resulted in increased transcription of CYP17 causing increased adrenal androgen synthesis in both normal, human adrenocortical tissue and in cultures of the adrenocortical tumor line H-295. In these same two *in vitro* systems insulin inhibited the forskolin (ACTH) stimulated synthesis of the transcription factor *nur77*, an action that results in decreased transcription of CYP21 mRNA, further directing adrenal steroidogenesis toward androgen vs cortisol biosynthesis.

**Figure 10.** Response of patient's serum corticosterone (ng/dl) to Ashwagandha 400 mg Twice Daily **0**

days and 17 days after starting ergocalciferol 50,000 IU daily.

days and 17 days after starting ergocalciferol 50,000 IU daily.

There is now considerable evidence that Vitamin D is an insulin sensitizer (28). We recently reported a patient with T2DM, classical 11- There is now considerable evidence that Vitamin D is an insulin sensitizer [28]. We recently reported a patient with T2DM, classical 11-hydroxylase deficiency, and severe Vitamin D deficiency [29].

hydroxylase deficiency, and severe Vitamin D deficiency (29). Metformin treatment was not initially an option in this patient as he had a life-threatening lower extremity infection with gangrene. Metformin would have increased his risk for developing dangerous lactic acidosis. His diabetes was, therefore, treated with basal/bolus insulin. Vitamin D replacement was begun using ergocalciferol 50,000 IU once a week. His serum 11-deoxycortisol fell from a baseline value of 2024 ng/dl (nl<76) to <20 ng/dl over a period of 28 days, while his serum 25-OH-vitamin D3 level rose concomitantly from a baseline value of 12 ng/ml (nl>30) to a level of 27 ng/dl on the 17th day of replacement (Figure 11). The 28 day Vitamin D sample was lost by the laboratory. It is known that the adrenal cortex has Vitamin D receptors (VDR's) (30). Thus, Vitamin D may also enhance the expression of adrenal steroidogenic enzymes via cross-talk. Metformin treatment was not initially an option in this patient as he had a life-threatening lower extremity infection with gangrene. Metformin would have increased his risk for developing dangerous lactic acidosis. His diabetes was, therefore, treated with basal/bolus insulin. Vitamin D replacement was begun using ergocalciferol 50,000 IU once a week. His serum 11-deoxycortisol fell from a baseline value of 2024 ng/dl (nl<76) to <20 ng/dl over a period of 28 days, while his serum 25-OH-vitamin D3 level rose concomitantly from a baseline value of 12 ng/ml (nl>30) to a level of 27 ng/dl on the 17th day of replacement (Figure 11). The 28 day Vitamin D sample was lost by the laboratory. It is known that the adrenal cortex has Vitamin D receptors (VDR's) [30]. Thus, Vitamin D may also enhance the expression of adrenal steroidogenic enzymes via cross-talk. There is now considerable evidence that Vitamin D is an insulin sensitizer (28). We recently reported a patient with T2DM, classical 11 hydroxylase deficiency, and severe Vitamin D deficiency (29). Metformin treatment was not initially an option in this patient as he had a life-threatening lower extremity infection with gangrene. Metformin would have increased his risk for developing dangerous lactic acidosis. His diabetes was, therefore, treated with basal/bolus insulin. Vitamin D replacement was begun using ergocalciferol 50,000 IU once a week. His serum 11-deoxycortisol fell from a baseline value of 2024 ng/dl (nl<76) to <20 ng/dl over a period of 28 days, while his serum 25-OH-vitamin D3 level rose concomitantly from a baseline value of 12 ng/ml (nl>30) to a level of 27 ng/dl on the 17th day of replacement (Figure 11). The 28 day Vitamin D sample was lost by the laboratory. It is known that the adrenal cortex has Vitamin D receptors (VDR's) (30). Thus, Vitamin D may also enhance the expression of adrenal steroidogenic enzymes via cross-talk.

**baseline day # 9 day # 17** Most recently, we have reported a patient whose non-classic 11-hydroxylase deficiency was improved by taking a combination of Vitamin D and the GLP-1 receptor agonist liraglutide (Figure 12) (31). GLP-1 receptor agonists improve insulin sensitivity by **Figure 11.** Changes in serum 11-deoxycortisol (left) as a function of changes in serum 25-OH-Vitamin D3 (right) at baseline and at 9 days and 17 days after starting ergocalciferol 50,000 IU daily.

prandial and fasting glucose levels and over time by weight, (visceral fat mass) reduction.

prandial and fasting glucose levels and over time by weight, (visceral fat mass) reduction.

5

**Figure 10.** Response of patient's serum corticosterone (ng/dl) to Ashwagandha 400 mg Twice Daily

There is now considerable evidence that Vitamin D is an insulin sensitizer (28). We recently reported a patient with T2DM, classical 11-

baseline

ashwaganda

Metformin treatment was not initially an option in this patient as he had a life-threatening lower extremity infection with gangrene. Metformin would have increased his risk for developing dangerous lactic acidosis. His diabetes was, therefore, treated with basal/bolus insulin. Vitamin D replacement was begun using ergocalciferol 50,000 IU once a week. His serum 11-deoxycortisol fell from a baseline value of 2024 ng/dl (nl<76) to <20 ng/dl over a period of 28 days, while his serum 25-OH-vitamin D3 level rose concomitantly from a baseline value of 12 ng/ml (nl>30) to a level of 27 ng/dl on the 17th day of replacement (Figure 11). The 28 day Vitamin D sample was lost by the laboratory. It is known that the adrenal cortex has Vitamin D receptors (VDR's) (30). Thus, Vitamin D may also enhance the

**Figure 11.** Changes in serum 11-deoxycortisol (left) as a function of changes in serum 25-OH-Vitamin D3 (right) at baseline and at 9

11-deoxycortisol

25-OH Vitamin D3

**Figure 12.** Response of Patient's Serum 11-Deoxycortisol (ng/dl; ref. range <42 ng/dl) to treatment with ergocalciferol & liraglutide

**Figure 10.** Response of patient's serum corticosterone (ng/dl) to Ashwagandha 400 mg Twice Daily Most recently, we have reported a patient whose non-classic 11-hydroxylase deficiency was improved by taking a combination of Vitamin D and the GLP-1 receptor agonist liraglutide (Figure 12) [31]. GLP-1 receptor agonists improve insulin sensitivity by suppressing the inappropriate secretion of the counter-regulatory hormone, glucagon, decreasing glucose toxicity by lowering post-prandial and fasting glucose levels and over time by weight, (visceral fat mass) reduction. Most recently, we have reported a patient whose non-classic 11-hydroxylase deficiency was improved by taking a combination of Vitamin D and the GLP-1 receptor agonist liraglutide (Figure 12) (31). GLP-1 receptor agonists improve insulin sensitivity by suppressing the inappropriate secretion of the counter-regulatory hormone, glucagon, decreasing glucose toxicity by lowering postprandial and fasting glucose levels and over time by weight, (visceral fat mass) reduction.

hydroxylase deficiency, and severe Vitamin D deficiency (29).

expression of adrenal steroidogenic enzymes via cross-talk.

days and 17 days after starting ergocalciferol 50,000 IU daily.

Metformin treatment was not initially an option in this patient as he had a life-threatening lower extremity infection with gangrene. Metformin would have increased his risk for developing dangerous lactic acidosis. His diabetes was, therefore, treated with basal/bolus Metformin treatment was not initially an option in this patient as he had a life-threatening lower extremity infection with gangrene. Metformin would have increased his risk for developing dangerous lactic acidosis. His diabetes was, therefore, treated with basal/bolus **Figure 12.** Response of Patient's Serum 11-Deoxycortisol (ng/dl; ref. range <42 ng/dl) to treatment with ergocalcifer‐ ol & liraglutide

#### value of 2024 ng/dl (nl<76) to <20 ng/dl over a period of 28 days, while his serum 25-OH-vitamin D3 level rose concomitantly from a baseline value of 12 ng/ml (nl>30) to a level of 27 ng/dl on the 17th day of replacement (Figure 11). The 28 day Vitamin D sample was insulin. Vitamin D replacement was begun using ergocalciferol 50,000 IU once a week. His serum 11-deoxycortisol fell from a baseline value of 2024 ng/dl (nl<76) to <20 ng/dl over a period of 28 days, while his serum 25-OH-vitamin D3 level rose concomitantly from a baseline value of 12 ng/ml (nl>30) to a level of 27 ng/dl on the 17th day of replacement (Figure 11). The 28 day Vitamin D sample was **C. Possible Mechanisms by Which Reducing Insulin Resistance Ameliorates Congenital Adrenal Hyperplasia 2.3. Possible mechanisms by which reducing insulin resistance ameliorates congenital adrenal hyperplasia**

hydroxylase deficiency, and severe Vitamin D deficiency (29).

hydroxylase deficiency, and severe Vitamin D deficiency (29).

**Figure 10.** Response of patient's serum corticosterone (ng/dl) to Ashwagandha 400 mg Twice Daily

There is now considerable evidence that Vitamin D is an insulin sensitizer [28]. We recently reported a patient with T2DM, classical 11-hydroxylase deficiency, and severe Vitamin D

**Figure 10.** Response of patient's serum corticosterone (ng/dl) to Ashwagandha 400 mg Twice Daily

Metformin treatment was not initially an option in this patient as he had a life-threatening lower extremity infection with gangrene. Metformin would have increased his risk for developing dangerous lactic acidosis. His diabetes was, therefore, treated with basal/bolus insulin. Vitamin D replacement was begun using ergocalciferol 50,000 IU once a week. His serum 11-deoxycortisol fell from a baseline value of 2024 ng/dl (nl<76) to <20 ng/dl over a period of 28 days, while his serum 25-OH-vitamin D3 level rose concomitantly from a baseline value of 12 ng/ml (nl>30) to a level of 27 ng/dl on the 17th day of replacement (Figure 11). The 28 day Vitamin D sample was lost by the laboratory. It is known that the adrenal cortex has Vitamin D receptors (VDR's) [30]. Thus, Vitamin D may also enhance the expression of adrenal

110 Contemporary Gynecologic Practice

deficiency [29].

expression of adrenal steroidogenic enzymes via cross-talk.

expression of adrenal steroidogenic enzymes via cross-talk.

days and 17 days after starting ergocalciferol 50,000 IU daily.

days and 17 days after starting ergocalciferol 50,000 IU daily.

**baseline day # 9 day # 17**

baseline and at 9 days and 17 days after starting ergocalciferol 50,000 IU daily.

**baseline day # 9 day # 17**

steroidogenic enzymes via cross-talk.

prandial and fasting glucose levels and over time by weight, (visceral fat mass) reduction.

prandial and fasting glucose levels and over time by weight, (visceral fat mass) reduction.

**Figure 11.** Changes in serum 11-deoxycortisol (left) as a function of changes in serum 25-OH-Vitamin D3 (right) at

insulin. Vitamin D replacement was begun using ergocalciferol 50,000 IU once a week. His serum 11-deoxycortisol fell from a baseline

11-deoxycortisol

 11-deoxycortisol 25-OH Vitamin D3

25-OH Vitamin D3

baseline

baseline ashwaganda

ashwaganda

 Most recently, we have reported a patient whose non-classic 11-hydroxylase deficiency was improved by taking a combination of Vitamin D and the GLP-1 receptor agonist liraglutide (Figure 12) (31). GLP-1 receptor agonists improve insulin sensitivity by suppressing the inappropriate secretion of the counter-regulatory hormone, glucagon, decreasing glucose toxicity by lowering post-

**Figure 12.** Response of Patient's Serum 11-Deoxycortisol (ng/dl; ref. range <42 ng/dl) to treatment with ergocalciferol & liraglutide

suppressing the inappropriate secretion of the counter-regulatory hormone, glucagon, decreasing glucose toxicity by lowering post-

**Figure 12.** Response of Patient's Serum 11-Deoxycortisol (ng/dl; ref. range <42 ng/dl) to treatment with ergocalciferol & liraglutide

11/8/2012 8/6/2012 5/3/2012

11/8/2012

8/6/2012 5/3/2012

**C. Possible Mechanisms by Which Reducing Insulin Resistance Ameliorates Congenital Adrenal Hyperplasia** 

Kelly et al. studied the effects of insulin in an *in vitro* human adrenocortical cell culture (32). They reported that steroidogenic factor-1 (SF-1) activity is up-regulated in vitro by insulin in the presence of forskolin (a functional analog of ACTH in this setting). Increased SF-1 synthesis, as well as increased binding of SF-1 to its response element, resulted in increased transcription of CYP17 causing increased adrenal androgen synthesis in both normal, human adrenocortical tissue and in cultures of the adrenocortical tumor line H-295. In these same two *in vitro* systems insulin inhibited the forskolin (ACTH) stimulated synthesis of the transcription factor *nur77*, an action that results in decreased transcription of CYP21 mRNA, further directing adrenal steroidogenesis toward androgen vs cortisol biosynthesis.

**C. Possible Mechanisms by Which Reducing Insulin Resistance Ameliorates Congenital Adrenal Hyperplasia** 

Kelly et al. studied the effects of insulin in an *in vitro* human adrenocortical cell culture (32). They reported that steroidogenic factor-1 (SF-1) activity is up-regulated in vitro by insulin in the presence of forskolin (a functional analog of ACTH in this setting). Increased SF-1 synthesis, as well as increased binding of SF-1 to its response element, resulted in increased transcription of CYP17 causing increased adrenal androgen synthesis in both normal, human adrenocortical tissue and in cultures of the adrenocortical tumor line H-295. In these same two *in vitro* systems insulin inhibited the forskolin (ACTH) stimulated synthesis of the transcription factor *nur77*, an action that results in decreased transcription of CYP21 mRNA, further directing adrenal steroidogenesis toward androgen vs cortisol biosynthesis.

lost by the laboratory. It is known that the adrenal cortex has Vitamin D receptors (VDR's) (30). Thus, Vitamin D may also enhance the **Figure 11.** Changes in serum 11-deoxycortisol (left) as a function of changes in serum 25-OH-Vitamin D3 (right) at baseline and at 9 lost by the laboratory. It is known that the adrenal cortex has Vitamin D receptors (VDR's) (30). Thus, Vitamin D may also enhance the **Figure 11.** Changes in serum 11-deoxycortisol (left) as a function of changes in serum 25-OH-Vitamin D3 (right) at baseline and at 9 Kelly et al. studied the effects of insulin in an *in vitro* human adrenocortical cell culture (32). They reported that steroidogenic factor-1 (SF-1) activity is up-regulated in vitro by insulin in the presence of forskolin (a functional analog of ACTH in this setting). Increased SF-1 synthesis, as well as increased binding of SF-1 to its response element, resulted in increased transcription of CYP17 causing increased adrenal androgen synthesis in both normal, human adrenocortical tissue and in cultures of the adrenocortical tumor line H-295. In these same two *in vitro* systems insulin inhibited the forskolin (ACTH) stimulated synthesis of the transcription factor *nur77*, an action that results in decreased transcription of CYP21 mRNA, further directing adrenal steroidogenesis toward androgen vs cortisol biosynthesis. Kelly et al. studied the effects of insulin in an *in vitro* human adrenocortical cell culture [32]. They reported that steroidogenic factor-1 (SF-1) activity is up-regulated in vitro by insulin in the presence of forskolin (a functional analog of ACTH in this setting). Increased SF-1 synthesis, as well as increased binding of SF-1 to its response element, resulted in increased transcription of CYP17 causing increased adrenal androgen synthesis in both normal, human adrenocortical tissue and in cultures of the adrenocortical tumor line H-295. In these same two *in vitro* systems insulin inhibited the forskolin (ACTH) stimulated synthesis of the transcription factor *nur77*, an action that results in decreased transcription of CYP21 mRNA, further directing adrenal steroidogenesis toward androgen vs cortisol biosynthesis. Thus, hyperinsulinemia would worsen the phenotypic/biochemical expression of 21-hydroxylase deficiency as well as magnify any other deficiencies of adrenal steroidogenic enzymes.

#### **2.4. Future directions in the treatment of congenital adrenal hyperplasia by reducing insulin resistance**

5

 Most recently, we have reported a patient whose non-classic 11-hydroxylase deficiency was improved by taking a combination of Vitamin D and the GLP-1 receptor agonist liraglutide (Figure 12) (31). GLP-1 receptor agonists improve insulin sensitivity by A number of drugs, herbs, naturally occurring compounds, as well as other therapeutic interventions have been shown to improve insulin sensitivity. While the efficacy of metformin and the thiazolidinediones in the treatment of NCAH is now established, it is still unknown if these agents could completely replace corticosteroids in classical CAH. Similarly, while we have shown in one patient that Vitamin D replacement can obviate the need for corticosteroids in a patient with classical 11-hydroxylase deficiency, we do not know if Vitamin D would work

5

as well in other classical forms of CAH or in CAH patients without vitamin D deficiency/ insufficiency. Randomized control trials will be needed to answer these important questions.

It is now recognized that dopamine receptor agonists have an in insulin-sensitizing effect [33, 34] and a formulation of the dopamine receptor agonist, bromocriptine, is now used to treat T2DM. Both bromocriptine and cabergoline, another dopamine receptor agonist, have been used to treat PCOS [35,36]. Since most insulin sensitizing treatments that are successful in PCOS turn out to be successful in treating NCAH, a pilot study using these agents in NCAH seems reasonable.

The bile acid binding resin, colesevelam, has been reported to improve insulin sensitivity, possibly by causing an increase in endogenous GLP-1 secretion [37,38]. This finding might be a basis for a pilot study using this agent to treat CAH.

The fat absorption blocking agent orlistat is approved as a weight loss aid when combined with diet and exercise in the U.S. in both a 60 gm over the counter form and a prescription only 120 mg form. In Canada it is approved for the treatment of T2DM. Panidis et al. reported that orlistat in combination with diet produced significant weight loss and improvement in insulin sensitivity in obese women, with or without PCOS [39]. In addition, serum testosterone levels were significantly improved in women with PCOS. Based on these data pilot studies of orlistat in NCAH should be performed. Stimulation of the CB-1 cannabinoid receptor has known orexic and euphoric effects, while its blockade with rimonabant has been associated with anorexic and dysphoric effects and results in weight loss, reduced insulin resistance, and improvements in glycemia and serum lipid levels [40] and has shown efficacy in PCOS patients [41]. Rimonabant was not approved in the U.S. and its approval was withdrawn in Europe because of a higher suicide risk due, presumably, to its dysphoric effect. The risk/benefit ratio of this class of agents might be improved by better patient selection, selective co-administration of an anti-depressant, treatment of hyperhomocysteinemia (which may play a role in depres‐ sion, or the development of selective cannabinoid receptor modulators, possessing the beneficial anorexic effect of the class without causing dysphoria.

The selective estrogen receptor modulators (SERM's), now in widespread clinical use, provide a model for such future development. Since CB-1 receptor blockers reduce insulin resistance, we might predict that they could ameliorate CAH.

Many, if not most, insulin resistant people have obstructive sleep apnea (OSA) [42]. Vgontzas et al. have reported that the inflammatory cytokines, TNF-α and IL-6 are elevated in patients with OSA, independently of obesity and that visceral fat was the primary parameter linked with OSA [42] and treatment with CPAP has been shown to improve insulin sensitivity in women with PCOS [43]. The fact that they found that OSA was more common in women with PCOS suggested a pathogenetic role of insulin resistance in OSA. The beneficial effect of a cytokine antagonist on excessive daytime sleepiness in obese, male apneics and on sleep disordered breathing in a general, random sample supports the hypothesis that cytokines and associated insulin resistance are mediators of excessive daytime sleepiness and OSA. Hamada et al have reported that with nasal CPAP in a CAH patient with OSA they were able to reduce the maintenance glucocorticoid dosage [44]. CAH patients, who have clinical features consis‐ tent with OSA, might benefit from undergoing a sleep study followed by a CPAP titration study if the initial sleep study is diagnostic. Alternatively, inhibitors of TNF-α and IL-6 might be useful adjuncts in the treatment of CAH.

as well in other classical forms of CAH or in CAH patients without vitamin D deficiency/ insufficiency. Randomized control trials will be needed to answer these important questions.

It is now recognized that dopamine receptor agonists have an in insulin-sensitizing effect [33, 34] and a formulation of the dopamine receptor agonist, bromocriptine, is now used to treat T2DM. Both bromocriptine and cabergoline, another dopamine receptor agonist, have been used to treat PCOS [35,36]. Since most insulin sensitizing treatments that are successful in PCOS turn out to be successful in treating NCAH, a pilot study using these agents in NCAH

The bile acid binding resin, colesevelam, has been reported to improve insulin sensitivity, possibly by causing an increase in endogenous GLP-1 secretion [37,38]. This finding might be

The fat absorption blocking agent orlistat is approved as a weight loss aid when combined with diet and exercise in the U.S. in both a 60 gm over the counter form and a prescription only 120 mg form. In Canada it is approved for the treatment of T2DM. Panidis et al. reported that orlistat in combination with diet produced significant weight loss and improvement in insulin sensitivity in obese women, with or without PCOS [39]. In addition, serum testosterone levels were significantly improved in women with PCOS. Based on these data pilot studies of orlistat in NCAH should be performed. Stimulation of the CB-1 cannabinoid receptor has known orexic and euphoric effects, while its blockade with rimonabant has been associated with anorexic and dysphoric effects and results in weight loss, reduced insulin resistance, and improvements in glycemia and serum lipid levels [40] and has shown efficacy in PCOS patients [41]. Rimonabant was not approved in the U.S. and its approval was withdrawn in Europe because of a higher suicide risk due, presumably, to its dysphoric effect. The risk/benefit ratio of this class of agents might be improved by better patient selection, selective co-administration of an anti-depressant, treatment of hyperhomocysteinemia (which may play a role in depres‐ sion, or the development of selective cannabinoid receptor modulators, possessing the

The selective estrogen receptor modulators (SERM's), now in widespread clinical use, provide a model for such future development. Since CB-1 receptor blockers reduce insulin resistance,

Many, if not most, insulin resistant people have obstructive sleep apnea (OSA) [42]. Vgontzas et al. have reported that the inflammatory cytokines, TNF-α and IL-6 are elevated in patients with OSA, independently of obesity and that visceral fat was the primary parameter linked with OSA [42] and treatment with CPAP has been shown to improve insulin sensitivity in women with PCOS [43]. The fact that they found that OSA was more common in women with PCOS suggested a pathogenetic role of insulin resistance in OSA. The beneficial effect of a cytokine antagonist on excessive daytime sleepiness in obese, male apneics and on sleep disordered breathing in a general, random sample supports the hypothesis that cytokines and associated insulin resistance are mediators of excessive daytime sleepiness and OSA. Hamada et al have reported that with nasal CPAP in a CAH patient with OSA they were able to reduce the maintenance glucocorticoid dosage [44]. CAH patients, who have clinical features consis‐

seems reasonable.

112 Contemporary Gynecologic Practice

a basis for a pilot study using this agent to treat CAH.

beneficial anorexic effect of the class without causing dysphoria.

we might predict that they could ameliorate CAH.

Curcumin is a component of the popular spice, turmeric. It has been reported to decrease levels of the inflammatory cytokine, TNF-α, which, in turn, downregulates the transcription factor PPAR-γ. Administration of curcumin results in up-regulation of PPAR-γ m-RNA and protein, which we would predict would improve insulin sensitivity [45]. Pilot studies with curcumin in CAH patients, would, therefore, be of interest given the absence of any known adverse effects. Other spices, herbs, and supplements known or suspected to have insulin sensitizing effects would also be worth exploring in CAH.

Somatostatin and its analogs-octreotide, octreotide LAR, and lanreotide partially suppress insulin secretion; reduction of hyperinsulinemia by this means could result in amelioration of both PCOS and CAH. Gambineri's group reported that octreotide-LAR improved the ovula‐ tion rate and hirsutism and showed nearly significant trends toward greater reductions in serum testosterone and androstenedione compared with placebo in dieting women with abdominal obesity and PCOS [46]. Pilot studies of these drugs in these two conditions, would, therefore, be of interest; because they reduce the secretion of growth hormone they would not be suitable for use in children or adolescents.

Phenytoin and diazoxide both decrease insulin secretion and have been reported to be helpful in treating some PCOS patients [47,48]. On this basis we might predict a response in CAH patients as well. In designing pilot studies with these agents, patients with pre-diabetes or low bone density should probably be excluded due to the diabetogenic potential of both drugs and the accelerated Vitamin D clearance attributed to the latter.

#### **2.5. Summary of treatment of CAH using insulin sensitizing approaches**


**•** The amelioration of CAH by insulin-sensitizing approaches suggests that, as in PCOS, insulin resistance is an integral part of the pathogenesis of the CAH's.
