Brand Name: Byetta
Generic Name: Exenatide

Dosage Form: Injection

Contents:

Description
Clinical Pharmacology
Clinical Studies
Indications and Usage
Contraindications
Precautions
Adverse Reactions
Overdosage
Dosage and Administration
Storage
How Supplied

Byetta (Exenatide) Patient Information (in plain English)

Description

Byetta^® (exenatide) is a synthetic peptide that has incretin-mimetic actions and was originally identified in the lizard Heloderma suspectum. Byetta enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, and alpha-glucosidase inhibitors.

Exenatide is a 39−amino acid peptide amide. Exenatide has the empirical formula C₁₈₄H₂₈₂N₅₀O₆₀S and molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below.

H - His - Gly - Glu - Gly - Thr - Phe - Thr - Ser - Asp - Leu - Ser - Lys - Gln - Met - Glu - Glu - Glu - Ala - Val - Arg - Leu - Phe - Ile - Glu - Trp - Leu - Lys - Asn - Gly - Gly - Pro - Ser - Ser - Gly - Ala - Pro - Pro - Pro - Ser - NH2

Byetta is supplied for subcutaneous (SC) injection as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide 30 days of twice daily administration (BID).

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Clinical Pharmacology

Mechanism of Action

Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. Exenatide is an incretin mimetic agent that mimics the enhancement of glucose-dependent insulin secretion and several other antihyperglycemic actions of incretins.

The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the known human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide promotes insulin release from beta cells in the presence of elevated glucose concentrations. When administered in vivo, exenatide mimics certain antihyperglycemic actions of GLP-1.

Byetta improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.

Glucose-dependent insulin secretion: Byetta has acute effects on pancreatic beta-cell responsiveness to glucose and leads to insulin release only in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia.

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First-phase insulin response: In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of Byetta at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with Byetta compared with saline (p

Figure 1: Mean (+SEM) Insulin Secretion Rate During Infusion of Byetta or Saline in Patients With Type 2 Diabetes and During Infusion of Saline in Healthy Subjects

Glucagon secretion: In patients with type 2 diabetes, Byetta moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand. However, Byetta does not impair the normal glucagon response to hypoglycemia.

Gastric emptying: Byetta slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.

Food intake: In both animals and humans, administration of exenatide has been shown to reduce food intake.

Pharmacokinetics

Absorption

Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. Mean peak exenatide concentration (C_max) was 211 pg/mL and overall mean area under the curve (AUC0-inf) was 1036 pg-h/mL following SC administration of a 10 mcg dose of Byetta. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 mcg to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of Byetta in the abdomen, thigh, or arm.

Distribution

The mean apparent volume of distribution of exenatide following SC administration of a single dose of Byetta is 28.3 L.

Metabolism and Elimination

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 h post-dose.

Special Populations

Renal Insufficiency

In patients with mild to moderate renal impairment (creatinine clearance 30 to 80 mL/min), exenatide clearance was only mildly reduced; therefore, no dosage adjustment of Byetta is required in patients with mild to moderate renal impairment. However, in patients with end-stage renal disease receiving dialysis, mean exenatide clearance is reduced to 0.9 L/h compared with 9.1 L/h in healthy subjects (see PRECAUTIONS, General).

Hepatic Insufficiency

No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic insufficiency. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is not expected to affect blood concentrations of exenatide (see Pharmacokinetics, Metabolism and Elimination).

Geriatric

Population pharmacokinetic analysis of patients (range from 22 to 73 years) suggests that age does not influence the pharmacokinetic properties of exenatide.

Pediatric

Exenatide has not been studied in pediatric patients.

Gender

Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide.

Race

Population pharmacokinetic analysis of patients including Caucasian, Hispanic, and Black, suggests that race has no significant influence on the pharmacokinetics of exenatide.

Obesity

Population pharmacokinetic analysis of obese (BMI ≥30 kg/m2) and non-obese patients suggests that obesity has no significant effect on the pharmacokinetics of exenatide.

Drug Interactions

Digoxin

Coadministration of repeated doses of Byetta (10 mcg BID) decreased the C_max of oral digoxin (0.25 mg QD) by 17% and delayed the Tmax by approximately 2.5 h; however, the overall steady-state pharmacokinetic exposure (AUC) was not changed.

Lovastatin

Lovastatin AUC and Cmax were decreased approximately 40% and 28%, respectively, and Tmax was delayed about 4 h when Byetta (10 mcg BID) was administered concomitantly with a single dose of lovastatin (40 mg) compared with lovastatin administered alone. In the 30-week controlled clinical trials of Byetta, the use of Byetta in patients already receiving HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles compared to baseline.

Lisinopril

In patients with mild to moderate hypertension stabilized on lisinopril (5 to 20 mg/day), Byetta (10 mcg BID) did not alter steady-state Cmax or AUC of lisinopril. Lisinopril steady-state T_max was delayed by 2 h. There were no changes in 24-h mean systolic and diastolic blood pressure.

Acetaminophen

When 1000 mg acetaminophen elixir was given with 10 mcg Byetta (0 h) and 1 h, 2 h, and 4 h after Byetta injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; C_max was decreased by 37%, 56%, 54%, and 41%, respectively; T_max was increased from 0.6 h in the control period to 0.9 h, 4.2 h, 3.3 h, and 1.6 h, respectively. Acetaminophen AUC, C_max and Tmax were not significantly changed when acetaminophen was given 1 h before Byetta injection.

Warfarin

Coadministration of repeat doses of Byetta (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers, delayed warfarin (25 mg) Tmax by about 2 h. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of warfarin were observed. Byetta did not change the pharmacodynamic properties (as assessed by INR response) of warfarin.

Pharmacodynamics

Postprandial Glucose

In patients with type 2 diabetes, Byetta reduces the postprandial plasma glucose concentrations (Figure 2).

Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of Byetta^a Treatment in Patients With Type 2 Diabetes Treated With Metformin, a Sulfonylurea, or Both (N = 54)

Fasting Glucose

In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, an immediate insulin release followed injection of Byetta. Plasma glucose concentrations were significantly reduced with Byetta compared with placebo (Figure 3).

Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a One-Time Injection of Byetta^a or Placebo in Fasting Patients With Type 2 Diabetes (N = 12)

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Clinical Studies

Use with metformin and/or a sulfonylurea

Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of Byetta in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea.

A total of 1446 patients were randomized in these three trials: 991 (68.5%) were Caucasian, 224 (15.5%) were Hispanic, and 174 (12.0%) were Black. Mean HbA1c values at baseline for the trials ranged from 8.2% to 8.7%. After a 4-week placebo lead-in period, patients were randomly assigned to receive Byetta 5 mcg BID, Byetta 10 mcg BID, or placebo BID before the morning and evening meals, in addition to their existing oral antidiabetic agent. All patients assigned to Byetta began a treatment initiation period with 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive Byetta 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the study.

The primary endpoint in each study was mean change from baseline HbA_1c at 30 weeks. Thirty-week study results are summarized in Table 1.

Table 1: Results of Thirty-Week Placebo-Controlled Trials of Byetta in Patients With Inadequate Glucose Control Despite the Use of Metformin, a Sulfonylurea, or Both

	Placebo BID	Byetta 5 mcg BID	Byetta 10 mcg* BID
*Byetta 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 6 months before the morning and evening meals. †p ≤0.05, treatment vs. placebo cp ≤0.0001, treatment vs. placebo §Patients eligible for the analysis with baseline HbA1c>7%.
	In Combination With Metformin
Intent-to-Treat Population (N)	113	110	113
HbA1c (%), Mean
Baseline	8.2	8.3	8.2
Change at Week 30	+0.1	−0.4â€	−0.8c
Proportion Achieving HbA1c≤7% §	13.0%	31.6%â€	46.4%â€
Body Weight (kg), Mean
Baseline	99.9	100.0	100.9
Change at Week 30	−0.3	−1.6â€	−2.8c
	In Combination With a Sulfonylurea
Intent-to-Treat Population (N)	123	125	129
HbA1c (%), Mean
Baseline	8.7	8.5	8.6
Change at Week 30	+0.1	−0.5â€	−0.9c
Proportion Achieving HbA1c≤7% §	8.8%	32.6%â€	41.3%c
Body Weight (kg), Mean
Baseline	99.1	94.9	95.2
Change at Week 30	−0.6	−0.9	−1.6â€
	In Combination With Metformin and a Sulfonylurea
Intent-to-Treat Population (N)	247	245	241
HbA1c (%), Mean
Baseline	8.5	8.5	8.5
Change at Week 30	+0.2	−0.6c	−0.8c
Proportion Achieving HbA1c≤7% §	9.2%	27.4%c	33.5%c
Body Weight (kg), Mean
Baseline	99.1	96.9	98.4
Change at Week 30	−0.9	−1.6â€	−1.6â€

HbA_1c

The addition of Byetta to a regimen of metformin, a sulfonylurea, or both, resulted in statistically significant reductions from baseline HbA_1c at Week 30 compared with patients receiving placebo added to these agents in the three controlled trials (Table 1). In addition, a statistically significant dose-effect was observed between 5-mcg and 10-mcg Byetta groups for the change from baseline HbA_1c at Week 30 in the three studies.

Fasting and Postprandial Glucose

Long-term use of Byetta in combination with metformin, a sulfonylurea, or both, reduced both fasting and postprandial plasma glucose concentrations in a statistically significant, dose-dependent manner through Week 30. A statistically significant reduction from baseline in both mean fasting and postprandial glucose concentrations was observed at Week 30 in both Byetta groups compared with placebo in data combined from the three controlled trials. The change in fasting glucose concentration at Week 30 compared with baseline was −8 mg/dL for Byetta 5 mcg BID and −10 mg/dL for Byetta 10 mcg BID, compared with +12 mg/dL for placebo. The change in 2-h postprandial glucose concentration following administration of Byetta at Week 30 compared with baseline was −63 mg/dL for 5 mcg BID and −71 mg/dL for 10 mcg BID, compared with +11 mg/dL for placebo.

Proportion of Patients Achieving HbA_1c≤7%

Byetta in combination with metformin, a sulfonylurea, or both, resulted in a greater, statistically significant proportion of patients achieving an HbA1c≤7% at Week 30 compared with patients receiving placebo in combination with these agents (Table 1).

Body Weight

In the three controlled trials, a decrease from baseline body weight at Week 30 was associated with Byetta 10 mcg BID compared with placebo BID in patients with type 2 diabetes (Table 1).

One-Year Clinical Results

The cohort of 163 patients from the 30-week placebo-controlled trials who completed a total of 52 weeks of treatment with Byetta 10 mcg BID had HbA1c changes from baseline of −1.0% and −1.1% at 30 and 52 weeks of treatment, respectively, with accompanying changes from baseline in fasting plasma glucose of −14.0 mg/dL and −25.3 mg/dL, and body weight changes of −2.6 kg and −3.6 kg. This cohort had baseline values similar to those of the entire controlled-trial population.

Use with a thiazolidinedione

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In a randomized, double-blind, placebo-controlled trial of 16 weeks duration, Byetta (n=121) or placebo (n=112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control. Randomization to Byetta or placebo was stratified based on whether the patients were receiving metformin. Patients assigned to placebo received placebo BID throughout the study. Byetta or placebo was injected subcutaneously before the morning and evening meals. Seventy-nine percent of patients were taking a thiazolidinedione and metformin and 21% were taking a thiazolidinedione alone. The majority of patients (84%) were Caucasian, 8% were Hispanic and 3% were Black. The mean baseline HbA1c values were similar for Byetta and placebo (7.9%). Byetta treatment was initiated at a dose of 5 mcg BID for 4 weeks then increased to 10 mcg BID for 12 more weeks.

Sixteen-week study results are summarized in Table 2. Compared to placebo, Byetta resulted in statistically significant reductions in HbA1c from baseline at Week 16. Treatment effects for HbA1c were similar in the two sub-groups defined by underlying treatment stratum (thiazolidinediones alone versus thiazolidinediones plus metformin). The change in fasting serum glucose concentration from baseline to Week 16 was statistically significant compared with placebo (−21 mg/dL for Byetta 10 mcg BID compared with +4 mg/dL for placebo).

Table 2: Results of 16-Week Placebo-Controlled Trial of Byetta in Patients With Inadequate Glucose Control Despite the Use of a Thiazolidinedione (TZD) or a Thiazolidinedione plus Metformin

Placebo BID	Byetta 10 mcg* BID
*Byetta 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 3 months before the morning and evening meals. †p <0.0001, treatment vs. placebo cPatients eligible for the analysis with baseline HbA1c>7%.
	In Combination With a TZD or a TZD plus MET
Intent-to-Treat Population (N)	112	121
HbA1c (%), Mean
Baseline	7.9	7.9
Change at Week 16	+0.1	−0.8â€
Proportion Achieving HbA1c≤7%c	16.2%	62.3%â€
Body Weight (kg), Mean
Baseline	96.9	97.5
Change at Week 16	−0.2	−1.5â€

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Indications and Usage

Byetta is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione, but have not achieved adequate glycemic control.

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Contraindications

Byetta is contraindicated in patients with known hypersensitivity to exenatide or to any of the product components.

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Precautions

General

Byetta is not a substitute for insulin in insulin-requiring patients. Byetta should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Patients may develop anti-exenatide antibodies following treatment with Byetta, consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals. Patients receiving Byetta should be observed for signs and symptoms of hypersensitivity reactions.

In a small proportion of patients, the formation of anti-exenatide antibodies at high titers could result in failure to achieve adequate improvement in glycemic control. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered.

The concurrent use of Byetta with insulin, D-phenylalanine derivatives, meglitinides, or alpha-glucosidase inhibitors has not been studied.

Byetta is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance Pharmacokinetics, Special Populations). In patients with end-stage renal disease receiving dialysis, single doses of Byetta 5 mcg were not well tolerated due to gastrointestinal side effects.

There have been rare, spontaneously reported events of altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring hemodialysis. Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function/hydration status and/or in patients experiencing nausea, vomiting, and/or diarrhea, with or without dehydration. Concomitant agents included angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, and diuretics. Reversibility of altered renal function has been observed with supportive treatment and discontinuation of potentially causative agents, including exenatide. Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.

Byetta has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Its use is commonly associated with gastrointestinal adverse effects, including nausea, vomiting, and diarrhea. Therefore, the use of Byetta is not recommended in patients with severe gastrointestinal disease. The development of severe abdominal pain in a patient treated with Byetta should be investigated because it may be a warning sign of a serious condition.

Hypoglycemia

In the 30-week controlled clinical trials with Byetta, a hypoglycemia episode was recorded as an adverse event if the patient reported symptoms associated with hypoglycemia with an accompanying blood glucose DOSAGE AND ADMINISTRATION).

Table 3: Incidence (%) of Hypoglycemia* by Concomitant Antidiabetic Therapy

		Byetta			Byetta			Byetta
	Placebo BID	5 mcg BID	10 mcg BID	Placebo BID	5 mcg BID	10 mcg BID	Placebo BID	5 mcg BID	10 mcg BID
	With Metformin			With a Sulfonylurea			With MET/SFU
Byetta and placebo were administered before the morning and evening meals.
Abbreviations: BID, twice daily; MET/SFU, metformin and a sulfonylurea.
*In three 30-week placebo-controlled clinical trials.
N	113	110	113	123	125	129	247	245	241
Hypoglycemia	5.3%	4.5%	5.3%	3.3%	14.4%	35.7%	12.6%	19.2%	27.8%

 

When used as add-on to a thiazolidinedione, with or without metformin, the incidence of symptomatic mild to moderate hypoglycemia with Byetta was 11% compared to 7% with placebo.

Byetta did not alter the counter-regulatory hormone responses to insulin-induced hypoglycemia in a randomized, double-blind, controlled study in healthy subjects.

Information for Patients

Patients should be informed of the potential risks of Byetta. Patients should also be fully informed about self-management practices, including the importance of proper storage of Byetta, injection technique, timing of dosage of Byetta as well as concomitant oral drugs, adherence to meal planning, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications.

Patients should be advised to inform their physicians if they are pregnant or intend to become pregnant.

Each dose of Byetta should be administered as a SC injection in the thigh, abdomen, or upper arm at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Byetta should not be administered after a meal. If a dose is missed, the treatment regimen should be resumed as prescribed with the next scheduled dose.

The risk of hypoglycemia is increased when Byetta is used in combination with an agent that induces hypoglycemia, such as a sulfonylurea. The symptoms, treatment, and conditions that predispose development of hypoglycemia should be explained to the patient. While the patient's usual instructions for hypoglycemia management do not need to be changed, these instructions should be reviewed and reinforced when initiating Byetta therapy, particularly when concomitantly administered with a sulfonylurea (see PRECAUTIONS, Hypoglycemia).

Patients should be advised that treatment with Byetta may result in a reduction in appetite, food intake, and/or body weight, and that there is no need to modify the dosing regimen due to such effects. Treatment with Byetta may also result in nausea, particularly upon initiation of therapy (see ADVERSE REACTIONS).

The patient should read the "Information for the Patient" insert and the Pen User Manual before starting Byetta therapy and review them each time the prescription is refilled. The patient should be instructed on proper use and storage of the pen, emphasizing how and when to set up a new pen and noting that only one setup step is necessary at initial use. The patient should be advised not to share the pen and needles.

Patients should be informed that pen needles are not included with the pen and must be purchased separately. Patients should be advised which needle length and gauge should be used.

Drug Interactions

The effect of Byetta to slow gastric emptying may reduce the extent and rate of absorption of orally administered drugs. Byetta should be used with caution in patients receiving oral medications that require rapid gastrointestinal absorption. For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 h before Byetta injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when Byetta is not administered. The effect of Byetta on the absorption and effectiveness of oral contraceptives has not been characterized.

Warfarin

In a controlled clinical pharmacology study in healthy volunteers, a delay in warfarin Tmax of about 2 h was observed when warfarin was administered 30 min after Byetta. No clinically relevant effects on Cmax or AUC were observed. However, since market introduction there have been some spontaneously reported cases of increased INR (International Normalized Ratio) with concomitant use of warfarin and Byetta, sometimes associated with bleeding.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection. Benign thyroid C-cell adenomas were observed in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in the two control groups and 14%, 11%, and 23% in the low-, medium-, and high-dose groups with systemic exposures of 5, 22, and 130 times, respectively, the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC).

In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay.

In mouse fertility studies with SC doses of 6, 68 or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating and females were treated 2 weeks prior to and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

Pregnancy

Pregnancy Category C

Exenatide has been shown to cause reduced fetal and neonatal growth, and skeletal effects in mice at systemic exposures 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Exenatide has been shown to cause skeletal effects in rabbits at systemic exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. There are no adequate and well-controlled studies in pregnant women. Byetta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 (organogenesis), cleft palate (some with holes) and irregular skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/kg/day, based on AUC.

In pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 (organogenesis), irregular skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths were observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

Nursing Mothers

It is not known whether exenatide is excreted in human milk. Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made whether to discontinue producing milk for consumption or discontinue the drug, taking into account the importance of the drug to the lactating woman. Studies in lactating mice have demonstrated that exenatide is present at low concentrations in milk (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing). Caution should be exercised when Byetta is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Byetta have not been established in pediatric patients.

Geriatric Use

Byetta was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or effectiveness were observed between these patients and younger patients.

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Adverse Reactions

Use with metformin and/or a sulfonylurea

In the three 30-week controlled trials of Byetta add-on to metformin and/or sulfonylurea, adverse events with an incidence ≥5% (excluding hypoglycemia; see Table 3) that occurred more frequently in Byetta-treated patients compared with placebo-treated patients are summarized in Table 4.

Table 4: Frequent Treatment-Emergent Adverse Events (≥5% Incidence and Greater Incidence With Byetta Treatment) Excluding Hypoglycemia*

Placebo BID N = 483 %	All Byetta BID N = 963 %
*In three 30-week placebo-controlled clinical trials.
Nausea	18	44
Vomiting	4	13
Diarrhea	6	13
Feeling Jittery	4	9
Dizziness	6	9
Headache	6	9
Dyspepsia	3	6

 

The adverse events associated with Byetta generally were mild to moderate in intensity. The most frequently reported adverse event, mild to moderate nausea, occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced nausea. Adverse events reported in ≥1.0 to <5.0% of patients receiving Byetta and reported more frequently than with placebo included asthenia (mostly reported as weakness), decreased appetite, gastroesophageal reflux disease, and hyperhidrosis. Patients in the extension studies at 52 weeks experienced similar types of adverse events observed in the 30-week controlled trials.

The incidence of withdrawal due to adverse events was 7% for Byetta-treated patients and 3% for placebo-treated patients. The most common adverse events leading to withdrawal for Byetta-treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew due to nausea and 0% due to vomiting.

Use with a thiazolidinedione

In the 16-week placebo-controlled study of Byetta add-on to a thiazolidinedione, with or without metformin, the incidence and type of other adverse events observed were similar to those seen in the 30-week controlled clinical trials with metformin and/or a sulfonylurea. No serious adverse events were reported in the placebo arm. Two serious adverse events, namely chest pain (leading to withdrawal) and chronic hypersensitivity pneumonitis, were reported in the Byetta arm.

The incidence of withdrawal due to adverse events was 16% (19/121) for Byetta-treated patients and 2% (2/112) for placebo-treated patients. The most common adverse events leading to withdrawal for Byetta-treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to nausea. Chills (n=4) and injection-site reactions (n=2) occurred only in Byetta-treated patients. The two patients who reported an injection-site reaction had high titers of anti-exenatide antibody.

Spontaneous Data

Since market introduction of Byetta, the following additional adverse reactions have been reported. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General: injection-site reactions; dysgeusia; somnolence, INR increased with concomitant warfarin use (some reports associated with bleeding).

Allergy/Hypersensitivity: generalized pruritus and/or urticaria, macular or papular rash, angioedema; rare reports of anaphylactic reaction.

Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis.

Renal and Urinary Disorders: altered renal function, including acute renal failure, worsened chronic renal failure, renal impairment, increased serum creatinine (see PRECAUTIONS).

Immunogenicity

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop anti-exenatide antibodies following treatment with Byetta. In most patients who develop antibodies, antibody titers diminish over time.

In the 30-week controlled trials of Byetta add-on to metformin and/or sulfonylurea, 38% of patients had low titer anti-exenatide antibodies at 30 weeks. For this group, the level of glycemic control (HbA1c) was generally comparable to that observed in those without antibody titers. An additional 6% of patients had higher titer antibodies at 30 weeks. In about half of this 6% (3% of the total patients given Byetta in the 30-week controlled studies), the glycemic response to Byetta was attenuated; the remainder had a glycemic response comparable to that of patients without antibodies.

In the 16-week trial of Byetta add-on to thiazolidinediones, with or without metformin, 9% of patients had higher titer antibodies at 16 weeks. Compared with patients who did not develop antibodies to Byetta, on average the glycemic response in patients with higher titer antibodies was attenuated.

The patient's glycemic response to Byetta should be monitored. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered.

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Overdosage

In a clinical study of Byetta, three patients with type 2 diabetes each experienced a single overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations. One of the three patients experienced severe hypoglycemia requiring parenteral glucose administration. The three patients recovered without complication. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

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Dosage and Administration

Byetta therapy should be initiated at 5 mcg per dose administered twice daily at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Byetta should not be administered after a meal. Based on clinical response, the dose of Byetta can be increased to 10 mcg twice daily after 1 month of therapy. Each dose should be administered as a SC injection in the thigh, abdomen, or upper arm.

Byetta is recommended for use in patients with type 2 diabetes mellitus who are already receiving metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione, and have suboptimal glycemic control. When Byetta is added to metformin or thiazolidinedione therapy, the current dose of metformin or thiazolidinedione can be continued as it is unlikely that the dose of metformin or thiazolidinedione will require adjustment due to hypoglycemia when used with Byetta. When Byetta is added to sulfonylurea therapy, a reduction in the dose of sulfonylurea may be considered to reduce the risk of hypoglycemia (see PRECAUTIONS, Hypoglycemia).

Byetta is a clear and colorless liquid and should not be used if particles appear or if the solution is cloudy or colored. Byetta should not be used past the expiration date. No data are available on the safety or efficacy of intravenous or intramuscular injection of Byetta.

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Storage

Prior to first use, Byetta must be stored refrigerated at 36°F to 46°F (2°C to 8°C). After first use, Byetta can be kept at a temperature not to exceed 77°F (25°C). Do not freeze. Do not use Byetta if it has been frozen. Byetta should be protected from light. The pen should be discarded 30 days after first use, even if some drug remains in the pen.

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How is Supplied

Byetta is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide. The following packages are available:

5 mcg per dose, 60 doses, 1.2 mL prefilled pen NDC 66780-210-07

10 mcg per dose, 60 doses, 2.4 mL prefilled pen NDC 66780-210-08

Rx ONLY

Manufactured for Amylin Pharmaceuticals, Inc., San Diego, CA 92121

Marketed by Amylin Pharmaceuticals, Inc. and Eli Lilly and Company
1-800-868-1190
http://www.Byetta.com

Byetta is a registered trademark of Amylin Pharmaceuticals, Inc.
© 2007 Amylin Pharmaceuticals, Inc. All rights reserved.

last updated 09/2007

Byetta (Exenatide) Patient Information (in plain English)

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

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The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.

back to: Browse all Medications for Diabetes

Comprehensive Lexapro information, including Lexapro side-effects, Lexapro dosage issues, more.

see important safety information

What is Lexapro

• Overview of Lexapro
• How Lexapro Works and What to Discuss with Your Doctor Before Starting Lexapro
• Taking Lexapro
• Lexapro Pharmacology - Usage, Dosage, Side-Effects (more technical)
• Lexapro Pharmacology - Usage, Dosage, Side-Effects (non-technical)
• Lexapro Side Effects and How to Cope With Them
• Tips for Handling the Side Effects of the Antidepressant Medications
• Drug Interactions and Overdose
• Helping Your Recovery From Depression and Anxiety

Online Depression Screening Test

• Online Depression Test (instantly scored)
• Online Generalized Anxiety Disorder Test (instantly scored)

Frequently Asked Questions

• About Lexapro
• Starting Lexapro and Dosage Issues
• Treatment Effectiveness
• Lexapro Side Effects and How to Cope With Them
• Lexapro Overdose, With Alcohol, People with Psychosis or Bipolar Disorder
• Women Taking Lexapro

Articles and News Stories

• Articles on Antidepressants and Depression Treatment Table of Contents
  • NIMH: Psychotherapy and Antidepressant Medications Work Best
  • Who Should Be Prescribing Your Antidepressants?
  • Too Many Quit Taking Antidepressants Too Soon
  • The Power of Social Support
• Articles on Generalized Anxiety Disorder (GAD) Table of Contents
  • What is Generalized Anxiety Disorder (GAD)
  • Definition, Signs, Symptoms of Generalized Anxiety Disorder (GAD)
  • Diagnosis of Generalized Anxiety Disorder (GAD)
  • Worry: How Much Is Too Much?
  • The Impact of Anxiety Disorders on the Family
  • Women and Anxiety: Twice as Vulnerable as Men
  • Anxiety Disorders in the Elderly

Related Communities

• HealthyPlace.com Depression Center
• HealthyPlace.com Anxiety - Panic Center

back to: Lexapro Information Center

Suggestions for managing antidepressant side-effects.

You can avoid some of the most common side effects of antidepressant medications with these tips:

• Eat cereals and other high-fiber foods (apples, salads, and celery) to reduce the chances of becoming constipated.
• Use sugarless gum and candy to relieve dry mouth. Take frequent sips of water throughout the day.
• Eat more frequent, smaller meals, rather than large meals, to help with nausea.
• Get up slowly from a lying or sitting position to reduce the possibility of feeling dizzy.
• Do not use any medications for common illnesses, such as the flu or allergies, without first speaking with your doctor in order to avoid any serious side effects.
• Let your doctor know if your side effects are not tolerable.
• Avoid caffeine or other stimulants that may cause problems with your sleep.
• Avoid drinking alcohol or taking other drugs.

Helping Recovery From Depression and Generalized Anxiety Disorder

next: LEXAPRO Drug Interactions and Overdose Issues

Newswise — While commonly perceived as a cry for attention from troubled teenage girls—self-injury is a dangerous and potentially life-threatening behavior that also occurs in adults of both genders.

"Stereotypically people think that self-injury happens only among teenagers and young women, but it also happens with older, middle-aged females and males," says Harrell Woodson, Ph.D., director of the Menninger Hope Program, which treats adults with mental illness. The Program is participating in a Clinic-wide initiative to learn more about self-injury and to develop new protocols to treat it since it is a frequent health issue among Menninger patients.

Older patients who injure themselves—commonly by cutting or burning the skin, or banging their heads repeatedly against the wall—are more difficult to treat, Dr. Woodson says. They may have been injuring themselves for such a long time that the behavior has become deeply ingrained.

Self-injury can be a sign of a psychiatric disorder and is common among persons suffering from severe borderline personality disorder, depression or psychosis. While the number of adults who purposely injure themselves is unknown, the behavior may be underreported because many persons who self-injure hide it from others.

Left untreated, self-injury and the mental illness that often accompanies it can become dangerous. While most persons who self-injure are not attempting suicide, they may accidentally kill themselves if their behavior goes too far.

"Self-injurious behavior can cause irreparable physical damage and can even lead to death, from cutting too deeply, getting an infection or going into shock," Dr. Woodson says.

Why would adults want to hurt themselves?

* To maintain a connection. Like teenagers, older adults may injure themselves in a negative bid for attention, sometimes a feature of severe borderline personality disorder. Persons with borderline personality disorder make frantic attempts to avoid abandonment. Cutting or otherwise harming themselves may seem like a way to keep their loved ones concerned and connected.

* To feel alive. Persons who are severely traumatized by sexual or physical abuse, neglect or a traumatizing event may detach themselves from their emotions and injure themselves so that they can regain feelings. "One of the ways they get back in touch with themselves is to feel pain," Dr. Woodson says. "It helps ground them when they feel they are falling apart."

* To distract. Self-injury helps some individuals distract or release themselves from their emotional pain, anxiety or depression, which in older adults may be caused by relationship problems with their spouse, significant other or children; job stress and other life issues facing adults.

* Because they must. Some persons who self-injure may have on-going symptoms of psychosis which causes them to break from reality and have auditory hallucinations (hear voices). "They are being commanded to hurt themselves," Dr. Woodson says. "They may hear a voice bargaining with them, telling them that if they don't bang their head 13 times, something bad will happen."

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Treatment

Because self-injury can be such a deeply ingrained behavior in older adults, helping patients find alternative coping mechanisms can be difficult. For patients, self-injurious behavior is often one of the few areas in their lives in which they feel a sense of control. Confronting them about the negative aspects of the behavior will not necessarily lead to behavior change.

Instead, mental health professionals work together with patients to determine how motivated they are to stop their self-injurious behavior. The desire for behavior change needs to come from the patient rather than as a demand from the mental health professional or family members, Dr. Woodson says. Motivational interviewing techniques put the majority of the responsibility for behavior change in the hands of the patient.

"With motivational interviewing, you capitalize on the patient's ambivalence—in terms of the pros and cons of continuing that behavior, in a non-confrontational way," Dr. Woodson continues. "Traditionally, admonishing people about the consequences of self-injurious behavior doesn't work very well."

The treatment team on Hope works with patients to discover what triggers a person to self-injure and to develop alternative coping strategies meaningful to that person. One alternative some mental health professionals suggest is to have patients place a rubber band around their arms. Snapping the rubber band creates some pain but no lasting injury.

Treatment may also include medication, especially when self-injurious behavior is tied to psychosis, and group therapy. Patients in group therapy discuss what they could do differently in response to particular stressors, situations, thoughts, and feelings rather than harming themselves. Groups are an effective form of treatment for self-injury, Dr. Woodson says because patients learn new insights and adaptive behaviors from their peers as well as receiving support and encouragement.

Source: Newswise

next: Overview of Pedophiles on the Web
~ all abuse library articles

Newswise — While commonly perceived as a cry for attention from troubled teenage girls—self-injury is a dangerous and potentially life-threatening behavior that also occurs in adults of both genders.

"Stereotypically people think that self-injury happens only among teenagers and young women, but it also happens with older, middle-aged females and males," says Harrell Woodson, PhD, director of the Menninger Hope Program, which treats adults with mental illness. The Program is participating in a Clinic-wide initiative to learn more about self-injury and to develop new protocols to treat it, since it is a frequent health issue among Menninger patients.

Older patients who injure themselves—commonly by cutting or burning the skin, or banging their heads repeatedly against the wall—are more difficult to treat, Dr. Woodson says. They may have been injuring themselves for such a long time that the behavior has become deeply ingrained.

Self-injury can be a sign of a psychiatric disorder and is common among persons suffering from severe borderline personality disorder, depression or psychosis. While the number of adults who purposely injure themselves is unknown, the behavior may be underreported because many persons who self-injure hide it from others.

Left untreated, self-injury and the mental illness that often accompanies it can become dangerous. While most persons who self-injure are not attempting suicide, they may accidentally kill themselves if their behavior goes too far.

"Self-injurious behavior can cause irreparable physical damage and can even lead to death, from cutting too deeply, getting an infection or going into shock," Dr. Woodson says.

Why would adults want to hurt themselves?

* To maintain a connection. Like teenagers, older adults may injure themselves in a negative bid for attention, sometimes a feature of severe borderline personality disorder. Persons with borderline personality disorder make frantic attempts to avoid abandonment. Cutting or otherwise harming themselves may seem like a way to keep their loved ones concerned and connected.

* To feel alive. Persons who are severely traumatized by sexual or physical abuse, neglect or a traumatizing event may detach themselves from their emotions and injure themselves so that they can regain feelings. "One of the ways they get back in touch with themselves is to feel pain," Dr. Woodson says. "It helps ground them when they feel they are falling apart."

* To distract. Self-injury helps some individuals distract or release themselves from their emotional pain, anxiety or depression, which in older adults may be caused by relationship problems with their spouse, significant other or children; job stress and other life issues facing adults.

* Because they must. Some persons who self-injure may have on-going symptoms of psychosis which causes them to break from reality and have auditory hallucinations (hear voices). "They are being commanded to hurt themselves," Dr. Woodson says. "They may hear a voice bargaining with them, telling them that if they don't bang their head 13 times, something bad will happen."

Treatment

Because self-injury can be such a deeply ingrained behavior in older adults, helping patients find alternative coping mechanisms can be difficult. For patients, self-injurious behavior is often one of the few areas in their lives in which they feel a sense of control. Confronting them about the negative aspects of the behavior will not necessarily lead to behavior change.

Instead, mental health professionals work together with patients to determine how motivated they are to stop their self-injurious behavior. The desire for behavior change needs to come from the patient rather than as a demand from the mental health professional or family members, Dr. Woodson says. Motivational interviewing techniques put the majority of the responsibility for behavior change in the hands of the patient.

"With motivational interviewing, you capitalize on the patient's ambivalence—in terms of the pros and cons of continuing that behavior, in a non-confrontational way," Dr. Woodson continues. "Traditionally, admonishing people about the consequences of self-injurious behavior doesn't work very well."

The treatment team on Hope works with patients to discover what triggers a person to self-injure and to develop alternative coping strategies meaningful to that person. One alternative some mental health professionals suggest is to have patients place a rubber band around their arms. Snapping the rubber band creates some pain but no lasting injury.

Treatment may also include medication, especially when self-injurious behavior is tied to psychosis, and group therapy. Patients in group therapy discuss what they could do differently in response to particular stressors, situations, thoughts and feelings rather than harming themselves. Groups are an effective form of treatment for self-injury, Dr. Woodson says, because patients learn new insights and adaptive behaviors from their peers as well as receiving support and encouragement.

Source: Newswise

Some of the misconceptions about attention deficit hyperactivity disorder (ADHD) include the following:¹

Myth	Fact
There is no such medical condition as ADHD.	ADHD is a medical disorder, not a condition of the child's will. A child with ADHD does not choose to misbehave.
ADHD is caused by bad parenting. All the child needs is good discipline.	ADHD is not caused by bad parenting, however, parenting techniques can often improve or worsen some symptoms.
ADHD is a life sentence.	Although ADHD symptoms usually continue into adulthood, the person learns ways to cope with the symptoms. People with ADHD have plenty of energy, are creative, and can often accomplish more than people who do not have the condition. 1
Having ADHD means the person is lazy or dumb.	ADHD has nothing to do with a person's intellectual ability. Some highly intelligent people have ADHD.
The diagnosis of ADHD is confirmed if certain medications (psychostimulants) have a positive effect on what seem to be symptoms of ADHD.	Children without ADHD respond to psychostimulants similarly to children with ADHD. A trial of medication is not used to diagnose the condition.
Medication for ADHD will make a person seem drugged.	Properly adjusted medication for ADHD sharpens a person's focus and increases his or her ability to control behavior.
Medication prescriptions for ADHD have greatly increased in the past few years because the condition is being overdiagnosed.	ADHD is estimated to affect approximately 3% to 7% of all school-age children in the United States.2 There is little evidence to support claims that ADHD is overdiagnosed and ADHD medications overprescribed.3
Psychostimulants are no longer useful after puberty.	Teens and adults with ADHD continue to benefit from medication treatment.
Children with ADHD are learning to use the condition as an excuse for their behavior.	ADHD is a disability. Children with ADHD have to learn ways to deal with their symptoms (inattention, impulsivity, and hyperactivity) that cause them to have difficulties in life.
Children outgrow ADHD.	About 70% to 80% of children with ADHD continue to have symptoms during their teen years and about 50% have symptoms into adulthood.4
If a child has ADHD, he or she can always be diagnosed in the health professional's office.	A child may not always show symptoms of ADHD, especially in an unfamiliar setting. Evaluating a child from one office observation may result in failure to recognize or diagnose symptoms.

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next: NIH: Research Backs ADHD Diagnosis in Children
~ adhd library articles
~ all add/adhd articles

References

Citations

1. Robin AL (1999). Attention-deficit/hyperactivity disorder in adolescents: Common pediatric concerns. Pediatric Clinics of North America, 46(5): 1027-1038.
2. American Psychiatric Association (2000). Attention-deficit and disruptive behavior disorders. In Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text rev., pp. 85-103. Washington, DC: American Psychiatric Association.
3. Brown RT, et al. (2001). Prevalence and assessment of attention-deficit/hyperactivity disorder in pimary care settings. Pediatrics, 107(3): 1-11.
4. National Institute of Mental Health (2003). Attention Deficit Disorder. NIH Publication No. 03-3572. Available online: http://www.nimh.nih.gov/publicat/adhd.cfm.

harm inflicted on intersexed children and their families by current medical practice

surgical harm attested to by adult intersexuals

debate on the question of childhood surgical intervention in intersexed births

The argument is always that the surgery makes the parents more comfortable. But counseling can do that too, and it is not irreversible in quite the same way as surgery. The question is: Do we use surgery to make parents more comfortable in the short run in the (often mistaken) belief that this will improve the psychological outcome for the intersexed child? Even though it may me an severe impairment of sexual function in adulthood?

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Intersexuality is essentially a cosmetic difference. Why, then, are minors denied the right to consent or refuse treatment? Why aren't the parents told to allow the child to grow up, to "wait and see?" Why is all the potential for choice erased in infancy? If parents were actually informed about what these cosmetic procedures entail, would they be less inclined to grant permission? Why is it that in this era of informed consent, no one protests when medical textbooks advise physicians to dissemble to parents about intersex diagnoses and "corrective" surgical procedures?

This question requires us to take a closer look at the meaning of "informed" consent. Currently intersex specialists simply assert that the child is ill, that surgery can cure the child, that the child's mental health will be at great risk without surgery, and that surgery presents no risk of harm. Parents assent, and the child is scheduled for the same genital surgery which many adult patients characterize as sexual mutilation.

Does the intersex specialist lie to the parents? From my point of view, yes. But from the physician's and parents' point of view, no. They actually believe -- a convenient belief -- that it is the health of the child that they are protecting. And as to the damage? Recently, I attempted to dissuade an acquaintance from permitting a clitoroplasty to be performed on her months-old infant . She responded, "Well, the clitoris isn't important to many women, so why should it matter? They'll just fix her little problem and be done with it." I wish I had proxy over her clit.

What I wish for most is that all cases of a primarily cosmetic nature be left alone until the minor has reached an age at which s/he can articulate his or her desires. I am not saying that surgery should never happen, but the prognosis at a purely physical level is much better if the body has already finished growing. And I would be inclined to argue that, illusory or not, the ability to choose for oneself favorably affects the results.

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The complaint of many intersexuals is that when gender reassignment is discovered, things get worse rather than better because their lives continue to be controlled by others, and they experience all sorts of additional traumas. These may be repeated, insensitive, and humiliating interviews; a frightening medical exam; a confrontation involving the perpetrator or the victim's family; an unpleasant placement experience; treatment that the child finds unhelpful or traumatic; and court testimony. Often the most problematic aspects of intervention are not knowing what is going to happen and having no say in decisions. It is important that the intervention not exacerbate the child's sense of powerlessness

Does sexual trauma have an impact on the mental and physical health of the victim?

Having been a victim of rape appears to significantly impact on the overall health of the victim. According to the 1988 report, "Rape in America," nearly one-third (31%) of all rape victims develop Post Traumatic Stress Disorder (PTSD) sometime during their lifetime. Additionally, researchers are beginning to notice a relationship between PTSD symptoms and an increase in physical health problems and reports of "not feeling well." What is Post Traumatic Stress Disorder (PTSD)? Post Traumatic Stress Disorder is a recurrent emotional reaction to a terrifying, uncontrollable, or life-threatening event. The symptoms frequently develop after a person's sense of safety and security is violated. Individuals with PTSD experience a variety of symptoms that often impede their daily lives. These may include sleep disturbances, nightmares, emotional instability, feelings of fear and anxiety around seemingly non-threatening situations, impaired concentration, and increased stress or problems in intimate and other interpersonal relationships. These reactions are common after a trauma and are pat of the initial adjustment process.

If you have never discussed your trauma with anyone and you are very frightened about talking about it now, and even wonder if you can. What can you do about this fear?

Unfortunately, this is a very common fear of women who have experienced sexual trauma. In fact, it is estimated that only sixteen (16) percent of the rapes that occur in this country are ever officially reported. Many of the reasons for this silence are based on society's stereotypes of women who have experienced sexual trauma. It is important to remember that health care professionals have become increasingly sensitized to the experience of sexual trauma and the impact it can have on the victim. As a result, they are more able to respond to the fears and anxieties that the victim may be experiencing. They will also understand the difficulty in discussing these reactions with another person and will be able to help the victims express themselves in a way that is most comfortable.

The Aftereffects of Sexual Trauma

Many veterans, who experienced an incident of sexual or personal trauma as a result of assault or harassment while they served on active military, have had no professional counseling and have never discussed it with anyone. The victims are embarrassed and have legitimate concerns about confidentiality. They may experience re-traumatization and have uncomfortable and frightening feelings when they recall the incident. Victims may have strong misgivings about the need or purpose for talking about the incident so long after it actually occurred. VA counselors know that people, who have been traumatized, can be successfully treated and that it is important to the overall health of the victim to talk though these upsetting and terrifying experiences.

• avoidance of places or objects which recall memories of the traumatic incident
• feelings that something is missing or not right
• depression, alcohol and substance abuse
• suicidal thoughts
• recurring and intrusive thoughts and dreams about the trauma incident
• non specific health problems
• relationship problems

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next: Sexual Differentiation
~ all inside intersexuality articles
~ all articles on gender

A Tampa Gender Identity Program (TGIP) Abstract

The human embryo has the potential to develop as either a male or female. In the absence of the chromosome, gonadal and genital differentiation proceeds along female lines with no proven role for fetal or maternal hormones in this process. In the presence of chromosomes (short arm, known as the sex determinant region of the chromosome), the embryo and bipotential gonad differentiate into a teste. Glycoprotein known as a mullerian inhibitory hormone induces the growth of the mullerian duct primordia which will otherwise form the uterus and fallopian tubes in the upper 2/3 of the vagina. The testosterone induces development of the wolffian duct into the epididymis, vas deferens, and seminal vesicle. The Dehydrotestosterone induces development of the penis, scrotal sac, and prostate. The hormonal difference between male and female is a quantitative phenomenon not a qualitative phenomenon. The male makes a lot more testosterone, converting some fraction to estradiol. The female makes much less testosterone, but converts a much larger fraction to estrogen. The numerous tissues such as liver, brain, and especially muscle and fat (more often during puberty in females) are very important in sexual development and differentiation, in part related to the aromatase. These hormones have profound somatic effects, not only controlled by genetic factors but also changes of activity of the aromatase in organs such as the placenta, contributing in the expression of breast tissue. Especially in females, the placenta plays a major role in producing placental estrogen needed to offset the fetal excess of androgens from the adrenal gland.

The development of Neuroendocrinology has determined the importance of the LHRH in sexual differentiation (pulsated secretion of the hypothalamic hormones) suppressed during fetal life. The male pituitary gland characteristically secretes both FSH and LH in a pulsatile, but a relatively constant and sustained manner in which has been called a tonic release, where in the adult female the pulsated secretion of FSH and LH is cyclic. The concept of a male pattern imprinted on sex centers of the hypothalamus (usually by male testosterone on the brain, not dependent on dehydrotestosterone), in different species, suggests sexually that the morphic nucleus in the preoptic area of the brain is perhaps not so much regulated by the amount of testosterone, but also by the levels of aromatization of testosterone to estradiol in the central nervous system. Studies of multiple genetic disorders clearly state and provide strong evidence that gender identity is not coded primarily by sexual chromosomes or gonadal steroids. The gender identity (18 to 30 months) is formed early in the postnatal years. Recent studies in males with defects in estrogen receptors in humans prove also the importance in male maturation in bones for normal growth and development.

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next: Multi-Dimensionality of Gender
~ all inside intersexuality articles
~ all articles on gender

Real People

A Secret Life by Steven Hammond

My name is Steven Hammond. I was born with a genital sexual birth defect. Because it was undetected at birth by both the doctor and my parents, I was raised the wrong sex. Alot of things in this life are hard to understand, but I think I have endured one of the most difficult things I can imagine to endure.

Children are born every day with different types of congenital birth defects. Some are born with no arms and no legs, some are born blind or deaf, or mentally retarded. It is hard to understand why these things happen, but in my case there were two things that happened. The first was being born with a sexual birth defect, which I now accept as just that. The second was being raised the wrong sex and having to change my whole life.

Only the God of this universe knows what I have had to endure both mentally and physically. He is the one who created me to be who I am, and he alone can understand my circumstances.

I'm sure that all the other people who have lived with birth defects must feel the same way. I hope that my story will enlighten people about sexual birth defects. Sexual birth defects are in a category of their own and are not to be confused with homosexuality, transsexualism, cross-dressing, or any situation where a physically normal person makes it their own choice to be different.

Steve Hammond is an ordinary guy. I drive a Jeep Cherokee pickup. I built the house where me and my wife, Sara Jane, live. I get up every day and go to my job at a warehouse in Berea, Kentucky. I wants to adopt a child and provide stability for my family. Like most of us, I dream of getting a little extra out of life. An ordinary guy. But I have an extraordinary story to tell.

Looking Beyond the Mountains
A book written by Steven Hammond.

Here is the story of how Linda Jean Hammond became Steven Hammond after surgery to correct a genital birth defect. Labeled female at birth, Steven Hammond lived for 25 years as a female -- a boy imprisoned in the trappings of a girl. This is the story of the life of Linda Jean and the birth of Steven at age 25. Click here to order Looking Beyond the Mountains.

Surprise

In 1981, Linda Jean Hammond (I was known as "Linda Jean"), 25, stepped into the Richmond office of Dr. William P. Grise a few minutes after he had opened. "It was the first time I'd revealed myself to a doctor. I'd been to a doctor for an ear ache and an infected hand but had never had a complete physical. I was very embarrassed and scared. I knew my secret was going to be revealed, a secret I'd held in all my life. "I figured he would know without asking me so many questions. That first time, I had a hard time talking." Grise remembers single-word answers to nearly every question, chipping away at Linda's wall of protection. Then came the examination.

Born Different

Linda Jean Hammond was born with a birth defect June 2, 1956, in Mary Rutan Hospital in Bellefontaine, Ohio. Dr. John B. Traul is listed as the physician. He has since died. If he or his nurses noticed anything unusual about the infant Hammond, they didn't press hard to do something about it. Linda went home untreated.

Six weeks later, my mother, Christine, and father, Floyd, moved our family of five children to Jackson County, Ky. Floyd's sister noticed "Linda used the bathroom funny" when she diapered the baby. She wanted to take Linda to a doctor. She told my father, but he wasn't around much. There wasn't money for the essentials then, much less medical help. A few years later, my parents divorced. My mother tried to raise the family the best she could, but there was barely enough to eat.

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There are memories of the poverty: "We woke up sometimes bleeding - me on the toes and my sister from the head - where rats bit us. We lived in houses with dirt floors. In the winter, it was always cold, so Mamma put us all in one bed together and covered us with a feather mattress so we could keep warm." I cried alot during those first years. My mother often thought something was wrong but couldn't pinpoint it and never said anything about it to me. I took comfort from my younger brother. Me and my younger brother Michael were the closest. I always wanted to play with his toys more that mine. He always had the guns. I always got the dolls.The Tomboy

Photos of Linda at the time (this one at age 10) show a cute, cheerful child, a little girl with chestnut hair cut in a pageboy. But all was not right. School was boring. There were school chums at Sand Gap Elementary School, but mostly Linda wanted to stay home alone, play softball or shoot basketball. Linda seemed a bit of a tomboy, but it only provoked a little teasing. By seventh and eighth grade, Linda became a cheerleader. "I wanted to be a part of the boy's basketball team, but I couldn't play. That was the only way I could be part of the team."

When I was 10, my mother married John R. Johnson. Life got much better. "He loved us alot. I have a biological real dad, but to me he is my real dad because I didn't know my other dad. He (Johnson) ran a filling station and taught all of us, but I guess I was the one most interested in electrical work, plumbing, carpentry, and mechanics. Mostly, he taught us alot of common sense."

What is Normal?

In Jackson County, where I grew up, pictures of naked men and women were hard to find, nor had I ever seen a naked man or a naked woman. So how could I know about normal development and about what male and female body parts were supposed to look like? At 11, I did tell my mother, "I get hard down there." I made my mother swear she wouldn't tell "John R.", as I called I my stepfather.

When I started at Jackson County High School in the early 1970's, the vague feelings got worse. Girlfriends talked about developing breasts and having menstrual periods, but I didn't develop. Periods never came. The anatomy was wrong, and it scared me. My mother wanted me to go to a doctor. I was terrified and refused.

Girls normally reach puberty between the ages of 11 and 17. My mother thought things would either get better or I would get sick and have to see a doctor. But my birth defect meant that wouldn't happen. I bullied Mamma into ignoring it.

Impulses of a Man

Linda went to work as a shipping clerk in a 13-acre warehouse. In one particularly striking photo from that time, Linda's hair falls well below the shoulders. Linda wore padded bras. Still, Linda's frustration kept building. Linda transferred from the clerk's job to loading trucks. To co-workers, Linda was "L.J. - the strongest woman they ever had to work with."

The guys on the dock didn't bother me much, and after work there was always softball. The trophies filled a room. By then, the frustration had become a full-fledged battle between the spiritual side of Linda and the angry person who wondered why God would make such a person. I was troubled by an attraction to women.

A co-worker said to Linda, "Jesus will save you." And the "big old tomboy who was always laughing and carrying on" grew quiet. I attended services in a white cinder block Baptist church. One day the preacher seemed to speak directly to me. He said the Bible said men shouldn't wear women's clothes and women shouldn't wear men's. My face burned. That was one of the last times I wore a skirt.

My attraction to women increased. A female friend became convinced my impulses were those of a man and urged me to visit a doctor. To do so, I had to show a body that had been hidden for so long. "Here I am, and I think I know what's going on but I'm confused. I think I could be both sexes, and I'm scared they're going to find out."

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The Reason Why

I didn't get a quick definitive answer during my first visit to the Richmond doctor. Dr. Grise called surgery and a specialist in urology at the University of Kentucky Chandler Medical Center. Dr. Grise told me, "When you feel like it, come in and let's talk about it. But I'm going to have to send you to somebody else." I tried to ignore it.

Thinking I was both sexes was one reason I'd rebelled and quit going to church. How can a person survive being both sexes when there's just male and female and that's how God created them? How could that person ever have a life?

When I didn't come back, Dr. Grise thought he'd lost his patient. More that a year passed between my first visit to the Dr. and the first trip to Lexington, Kentucky to see Dr. J. William McRoberts.

I drank some and bills piled up. There was a feeling of disarray. I wanted a home, a life. The confusion was more painful than the fear of exposure. Finally, the will to do something won out.

I was still really in mystery, and was looking forward to seeing Dr. McRoberts. First they took a long history of my life. There were several exams by different doctors until McRoberts arrived. But this time, there was no lying on the back, legs spread and feet in stirrups. It was very embarrassing for me, and I think that's true with anyone, but I found hope. Dr. McRoberts diagnosed my problem right away. Tests followed, but they were only to make sure nothing had been missed. The cause of my lifelong confusion was a birth defect.

Linda Hammond was born male. He had male sex organs. But his development had been incomplete, and at birth he'd been confused with a female. The male hormones produced by male glands had given him normal male desires.

Dr. McRoberts explained the medical term was male pseudo (or false) hermaphrodite. The term has caused much confusion. It simply means that Linda was male, always male, but that his untreated appearance could be confused with someone who had the characteristics of both sexes.

Confusing sexual characteristics occur in perhaps one in every 1,000 births, Dr. McRoberts said. Some of the causes can be explained. For instance, a malfunctioning adrenal gland can cause a female to develop genitalia that look like those of a male. Other causes are not as well understood, and with the exception of the reproductive system, the patient is otherwise normal.

Most of the time, these problems are detected at birth. The problem is corrected, the baby goes home either a boy or a girl. Sometimes the birth defect is discovered later. As a surgeon specializing in urology, Dr. McRoberts had seen babies with confusing sex characteristics hundreds of times before, but rarely in anyone over the age of 8. Only once before had he seen it in a teenager. At 26, I was the oldest patient with such a problem whom Dr. McRoberts had ever seen.

The Confusion and the Courage

The confusion began before my birth. A developing embryo has the potential to be either male or female. Each embryo has wolffien ducts - a tube with the potential to form the male reproductive system - and mullerian ducts that can develop into the female reproductive system. The sex chromosome - contributed by the father - causes secretion of the hormones that determine whether the wolffian male duct or the mullerian ducts will predominate. An embryo becomes male because of the secretion of a hormone (testosterone) that develops the wolffian ducts and inhibits the mullerian. All the hormones and all of the events must be just right.

For me, the final stage was incomplete. I had all the normal male equipment, but my testicles remained inside my body and produced male hormones. My penis was covered by the folds of skin that normally join together to form the scrotal sac. The urethral opening to my bladder was malformed. But enough was right so the condition could be surgically corrected to give normal male sexual function.

But for those first few weeks after my visit to Dr. McRoberts, I didn't worry about the four operations to come. I was relieved that my confusion was over. I knew Id always been male.

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Dr. McRoberts signed statements to substantiate the fact. With the help of a lawyer, Linda Jean Hammond became Steve Hammond. I had no trouble accepting it myself. I knew I'd be headed for a hard road, but except for the surgery, I never did take off work, never did have mental help. I look back on it and wonder, "How did I ever have the courage to go through it?"

I called my mother, the only one who knew my secret. She remembered that as a child, I'd had boyish behavior and boyish hands and feet. Still it surprised her. My mother said, "I guess it was my fault letting you have your way (not seeing a doctor). But when your were a baby, there was no way you could tell. I don't know, I guess you accept children the way they are."

John R., my stepfather, cried when he found out - not because he was ashamed, but because he remembered how Steve had helped him in the garage all those years. He sensed the embarrassment I would face in explaining my new identity and how some would refuse to understand. "'What do you reckon happened to Linda?' they'll ask. 'What went wrong?' I'll explain it and tell them all I know about it and then, maybe three months later, they'll ask me to explain it again", my stepfather said. "There's just no use trying to explain it to some people. They just hear what they want to hear."

My mother told my brothers and sister. They seemed to accept my new identity. They never asked me about it. Right after the doctor said I was a man, it was like God was waiting for me to do this all my life. My life really unfolded like a page.

Afterward

I woke up after the first operation in the hospital's gray-and blue tile recovery room. There was Dr. McRoberts sitting next to me in a wooden rocking chair writing his surgical notes, wearing a paisley surgical cap and a blue surgical scrub suit. "Dr. McRoberts, I believe God has blessed your hands," I told him. Medical insurance paid most of the bills. And the good doctor waived the rest.

I have distanced myself from the first 25 years of my life. I threw away my softball trophies and many other reminders of my past. Then I had to convince others that I was a man. As Linda, I had used the women's bathroom at work, and now I would have to use the men's. I had to prove to the personnel officer that I was a man and had changed my name.

The first time I walked into the men's room, there were 10 men inside, some of them snickering. Generally, my co-workers were supportive. But once a man cursed me, called me names and tried to get me to fight. I, determined to respond as a Christian, wouldn't answer, wouldn't fight unless I was hit. My response so affected my tormentor that he, too, became a Christian. Some co-workers have said I'm one of the strongest people they've ever known because I had the nerve. But one man still calls me Linda. My friends knew what I was going through and gave their prayers and help.

Getting Married

Sara Jane Van Winkle and I first met when she accompanied a friend who dropped by my apartment. The friend was worried "about all that Steve was going through" and wanted to check and see if I was all right. Sara Jane is from Rockcastle County and never knew me as Linda. Sara Jane said, "There he was, just another guy in a T-shirt and sweat pants. He seemed a little bit shy. I did most of the talking. But he was open and honest about things.

I always admired that in people. We just talked awhile, got acquainted and that was it." As our relationship developed, I explained everything to Sara Jane. I told her I could have sex but was sterile. Most of her friends accepted me without question.

I married Sara Jane in 1983, a few months after my visit to Dr. McRoberts. I was 26. She was 27. I decided to tell my story because I want people to know this problem was a birth defect - not a sex change. I want to help anyone who may be going through what I went through. I'm planning to write a book about my experiences.

Looking Beyond the Mountains
A book written by Steven Hammond..

Here is the story of how Linda Jean Hammond became Steven Hammond after surgery to correct a genital birth defect. Labeled female at birth, Steven Hammond lived for 25 years as a female -- a boy imprisoned in the trappings of a girl. This is the story of the life of Linda Jean and the birth of Steven at age 25. Click here to order Looking Beyond the Mountains.

 

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next:   Guide to Medical Intersexuality Vocabulary
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from the Merck Manual

How to Understand Medical Writing on Intersex

ambiguous genitalia

Genitalia that refuse to declare their sex to doctors--no doubt on the principle that under interrogation by the enemy you should give only name, rank, and serial number.

androgen

Andro=male; gen=making. Androgens are administered to infants to prevent their becoming androgynes. See testosterone.

androgen insensitivity

The condition of infants who callously refuse to respond to testosterone treatment; the cause of many an endocrinologist's hurt feelings.

circumcision

A mass-market edition of intersexed surgery, priced for the common man. The reasons for circumcision are too numerous to treat here, but T.V.N. Persaud of the University of Manitoba recites one ingenious opinion:

Some conditions, such as phimosis, often lead to circumcision at a later age that could have been prevented if it had been performed earlier.

Physicians thus exhibit the same prescience as the Monopods in C. S. Lewis's The Chronicles of Narnia, who boiled potatoes before planting them in order to save doing it when they were dug up.

clitoral recession

See female genital mutilation. Despite Webster's false cognate, "recession" is derived from "rescission," the noun form of the verb "rescind." Endocrinologists, like certain Congressmen, like to rescind budgets they feel are too large, even when this means cutting off essential services.

clitoromegaly

Micropenis in the female. A longer definition would be superfluous, since this condition is apt to be cut off before the patient can pronounce it.

cryptorchidism

A condition in which the testes (-orchid) are hidden (crypto-). Hidden from whom? Obviously, from the doctors. Cryptorchidism is thus practiced by those discriminating infants who do not wish to put pearls before swine.

distress

A condition caused in parents when their intersexed children go unmutilated.

estrogen

1. A character in Samuel Beckett's Waiting for Godot, who was just pining away for a doctor to come change his sex.

2. A character in Ursula Le Guin's The Left Hand of Darkness, who bloody well wasn't.

female

1. A male intersexual when the endocrinologist is through with him.

2. A female intersexual whom the urologist has not seen yet.

female genital mutilation (FGM)

The scarring or removal of the clitoris, performed by witch doctors and condemned by all right-thinking people. If the clitoris is a bit larger than average, however, it is performed by accredited surgeons and covered by all major insurance plans.

gynecomastia

Enlargement of the breasts in a patient whom we have decided to call male. In a patient whom we have decided to call female, the same trait is called "excellent breast development."

hypertrophy

Literally, too much meat. How much is too much? More, madam, than your sister has; less, sir, than you will have when we are through.

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hypogonadotropic hypogonadism

A condition in which the gonads are small owing to a lack of the chemical signals that activate them. To be distinguished from hypergonadotrophic hypogonadism, in which the gonads are small owing to an excess of the chemical signals that activate them. The progress of medical science makes possible these ingenious explanations of formerly murky phenomena.

hypospadias

A condition in which the meatus of the penis exits elsewhere than the tip. The etymology of this term is worthy of great meditation: hypo=too little; spadix is the Latin for sword. If only the infant's sword were larger, he would be able to fight off the surgeon.

idiopathic

Found in solitude. A condition that boors never allow to persist in women or in symptoms.

Contrary to previous report, idiopathy does not mean "stupid medicine," there being no need of a special term to identify that thriving Science.

Klinefelter's Syndrome

One of that large class of syndromes named for people who did not have the syndromes. Even Lou Gehrig's Disease has been renamed for some doctor who probably couldn't even hold a bat.

lusus naturae

A freak of nature. It may at first surprise the reader that this term is not applied to people who cut up perfectly healthy genitals; but while that behavior is certainly freakish, nature has nothing to do with it.

male

See female. Whatever you may say of medical Fascism, it does make the males run on time.

micropenis

Clitoromegaly in the male. Cutting off the micropenis and rearing the child as female is a common way of producing a satisfactory psychological adjustment;

For it's a fact the whole world knows That Pobbles are happier without their toes.

Edward Lear

presenting

Having. As in, "The infant presented a hypospadiac micropenis" (said by doctors) or "The jogger presented a large wallet" (said by muggers).

primary hypogonadism

Primary hypogonadism reduces the body's sex hormones due to undeveloped testes or ovaries; see micropenis, which it sometimes causes.

It is not clear to the compiler of this Manual why some doctors feel that primary hypogonadism should be followed by a genital election.

pseudohermaphrodite

Pseudo=false; a pseudohermaphrodite is one whose falsely ambiguous genitals cruelly mislead the doctor into hopes of publication. So, at least, says pseudoscience.

res ipsa loquitur

Legal, not medical, Latin: "the thing speaks for itself." A sponge left in a patient's body speaks for itself, and is well paid to do so; but for the sex organ removed from the body, nobody will speak.

rights

Wrongs. In medical literature, the 'rights' of the intersexed refer exclusively to their right to be modified, never to any right to remain as they are. For example, one text calls for hypospadias to be "corrected" even when it is purely cosmetic, on the grounds that "by the age of five every boy has the right to be a 'pointer' and not a 'setter'."

stenosis

Narrowness. A condition of meatuses and minds.

surgical sex reassignment (infant)

Making a sow's ear out of a silk purse. Known to cause deafness.

testosterone

An androgen taking its name from the test in which it is applied to a micropenis. Micropenises that do not grow must be cut off; if they do grow then no further treatment is needed. Compare the water ordeal, beloved of witch-hunters, in which witches that float must be drowned, while those that sink may remain as they are. We Americans may be justly proud at the advances in our enlightened Society.

urologists

Those benefactors of humanity who, with considerable difficulty, distinguish intersexed infant boys from intersexed infant girls. These infants, when grown, may with equal difficulty distinguish urologists from butchers.

I pray that some day I will have the means to repay, in some measure, the American Urological Association for all they have done for my benefit. I am having some trouble, though, in connecting the timing mechanism to the fuse.

Quoted by Megan Holmes, from a letter by an anonymous intersexual

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