17-Hydroxyprogesterone

17-Hydroxyprogesterone (17-OHP) is a vital hormone in the steroidogenesis pathway.  

Produced primarily in the adrenal glands and to some extent in the gonads, 17-OHP is synthesized from pregnenolone and is an intermediate in the production of glucocorticoids and sex steroids. Its levels and metabolism are critical for maintaining endocrine health and physiological balance.

The measurement of 17-OHP levels in the blood is an essential diagnostic tool, particularly in identifying congenital adrenal hyperplasia (CAH), a genetic disorder affecting steroidogenesis which leads to cortisol deficiency and an overproduction of androgenic steroids. 

Given its pivotal role in hormone regulation, understanding 17-OHP's pathways not only aids in diagnosing and managing disorders like CAH but also underscores the importance of maintaining hormonal balance. 

This article explores the synthesis and function of 17-OHP, its role in health and disease, how it is measured in the laboratory, and clinical implications of high and low levels.  

What is 17-Hydroxyprogesterone?

17-Hydroxyprogesterone is a steroid hormone that plays a crucial role in the synthesis of other steroid hormones, particularly cortisol, and androgens. 

Production and Significance of 17-Hydroxyprogesterone

17-Hydroxyprogesterone (17-OHP) is a precursor hormone synthesized in the adrenal glands and gonads, as well as in the placenta during pregnancy.  

Cholesterol serves as the initial precursor for steroid hormone synthesis, with several enzymatic steps converting cholesterol to 17-Hydroxyprogesterone. 

17-OHP is produced from progesterone by the enzyme 17-alpha hydroxylase.   

It serves as an intermediate in the biosynthesis of cortisol, a vital hormone involved in stress response, metabolism, and immune function.  17-OHP is converted to cortisol by the CYP family of enzymes, notably 21-alpha hydroxylase and 11-beta hydroxylase.  [5.]

Additionally, 17-Hydroxyprogesterone is a precursor to androgens including testosterone and dihydrotestosterone (DHT), which play essential roles in male and female reproductive health, sexual development, and secondary sexual characteristics.  

17-OHP enters the androgenic family of hormones when it is converted to androstenedione, an androgen, by another member of the CYP family of enzymes, 17, 20 lyase.  [5.]

17-OHP is primarily a precursor to cortisol and androgens, although it also possesses its own biological activity that may become clinically relevant in congenital adrenal hyperplasia (CAH).  [13.] 

Dysregulation of the steroidogenesis pathway can lead to elevations in 17-Hydroxyprogesterone levels that indicate the presence of various endocrine disorders such as congenital adrenal hyperplasia (CAH).

17-Hydroxyprogesterone in Females  [8.] 

17-Hydroxyprogesterone is primarily a hormone intermediary, but it indirectly plays a significant role in female reproductive health, influencing menstrual cycles, fertility, and pregnancy.

In females, 17-OHP levels fluctuate across the menstrual cycle, increasing after ovulation, which can influence other steroid hormone levels indirectly affecting fertility and menstrual regularity.

Menstrual Cycle Regulation

During the menstrual cycle, 17-Hydroxyprogesterone levels fluctuate in response to hormonal changes orchestrated by the hypothalamic-pituitary-ovarian (HPO) axis.  Following ovulation, 17-Hydroxyprogesterone levels rise during the luteal phase of the menstrual cycle under the influence of luteinizing hormone (LH) and progesterone. 

This increase in 17-Hydroxyprogesterone promotes the development and maintenance of the endometrial lining, preparing the uterus for potential embryo implantation.  Low levels of 17-Hydroxyprogesterone in the luteal phase may signal an alteration in progesterone production. 

Fertility and Pregnancy

In the context of fertility and pregnancy, 17-Hydroxyprogesterone levels follow progesterone levels: therefore they are a sign of overall hormonal balance and of a woman’s physiologic capacity for supporting early gestation and maintaining the uterine environment conducive to embryo implantation and fetal development. 

During pregnancy, 17-Hydroxyprogesterone is produced by the placenta, serving as a precursor for placental steroid hormone synthesis.  [14.]  Adequate 17-Hydroxyprogesterone levels are essential for preventing miscarriage and supporting the growth and development of the fetus. 

Clinical Considerations

Measurement of 17-Hydroxyprogesterone levels in females is often performed in the context of evaluating menstrual irregularities, infertility, hirsutism and pregnancy-related complications.  

Low levels of 17-Hydroxyprogesterone may contribute to menstrual disorders such as irregular cycles, anovulation, and luteal phase defects. In cases of infertility, assessing 17-Hydroxyprogesterone levels can help identify underlying hormonal imbalances affecting reproductive function. 

Additionally, monitoring 17-Hydroxyprogesterone levels during pregnancy may aid in the early detection of placental dysfunction and other pregnancy-related complications, allowing for timely intervention and management. 

17-Hydroxyprogesterone and Congenital Adrenal Hyperplasia

Definition of Congenital Adrenal Hyperplasia  [12.]

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by various enzyme defects in the adrenal glands that disrupt steroid hormone synthesis, including glucocorticoids, mineralocorticoids, and sex steroids. 

These deficiencies arise from mutations in genes encoding these enzymes, primarily impacting the production of cortisol and, to a lesser extent, aldosterone. 

Because cortisol production is critical for regulating various bodily functions including metabolism and the immune response, its deficiency can lead to symptoms ranging from mild to life-threatening.

The lack of cortisol stimulates the pituitary gland to release more adrenocorticotropic hormone (ACTH), which in turn causes the adrenal glands to enlarge and produce excess androgens.

The most common form is due to a deficiency in 21-hydroxylase which affects 90%-95% of cases and leads to excessive androgen production and a spectrum of clinical presentations from ambiguous genitalia at birth to non-classic forms with later onset including early signs of puberty in children, and fertility issues in adults.

CAH can also result in severe salt-wasting forms which increase neonatal morbidity and mortality, making early diagnosis and treatment essential. 

Depending on the specific enzyme affected and the severity of the deficiency, CAH can be categorized as either classical (severe) or non-classical (mild). Treatment typically involves hormone replacement therapy to correct the deficiencies and manage symptoms.

Newborn Screening for Congenital Adrenal Hyperplasia

Newborn screening for 17-hydroxyprogesterone, which is used to detect congenital adrenal hyperplasia (CAH), is widely implemented but not universally conducted in every country. 

In the United States, it is included in the routine newborn screening panel as a heel stick in all states, helping to identify infants with CAH early so that treatment can begin promptly.  [7.]

However, the inclusion of this test in newborn screening programs varies globally, depending on the healthcare policies and resources of each country. Some countries may have different protocols or may not include this test in their standard newborn screening.

Elevated levels of some steroid hormones including 17-OHP have been noted in the amniotic fluid of unborn babies.  [6.]

Causes of Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is primarily caused by genetic defects in enzymes that are crucial for cortisol synthesis.  The different enzyme deficiencies that lead to various forms of CAH include:

21-Hydroxylase Deficiency  [4.]

An autosomal recessive condition, this is the most common cause of CAH, accounting for about 90-95% of all CAH cases. 

It affects the conversion of 17-hydroxyprogesterone to 11-deoxycortisol and progesterone to deoxycorticosterone, ultimately manifesting in impaired cortisol synthesis in the adrenal glands. This deficiency prompts the need for lifelong glucocorticoid and mineralocorticoid replacement therapy. 

Effective management of this condition relies heavily on an interprofessional healthcare team to optimize patient outcomes. 

Early diagnosis through newborn screening, which measures 17-hydroxyprogesterone levels, is crucial for preventing severe complications such as adrenal crisis and virilization. 

The management strategy includes regular monitoring and adjusting hormone therapy to mitigate symptoms and prevent long-term complications.

11β-Hydroxylase Deficiency  [3.]

The second most common cause, affecting the conversion of 11-deoxycortisol to cortisol and deoxycorticosterone to corticosterone.

CAH due to 11β-hydroxylase deficiency (11βOHD) is a rare, autosomal recessive form, constituting only 0.2-8% of all CAH cases.  

A case involving a three-year-old girl diagnosed with classical CAH illustrates this condition's complexity: despite receiving regular hydrocortisone treatment, she presented with atypical genitalia and persistent hypertension. Genetic analysis revealed a novel homozygous mutation (c.53dup p.(Gln19Alafs*21)) in the CYP11B1 gene, confirming 11βOHD. 

This case underscores the importance of considering 11βOHD in CAH patients with persistent hypertension, as typical biomarkers might not always align with this diagnosis.

3β-Hydroxysteroid Dehydrogenase Deficiency  [2.]

3-beta-hydroxysteroid dehydrogenase (3ß-HSD) deficiency is an autosomal recessive congenital adrenal hyperplasia (CAH) that impacts the conversion of pregnenolone to progesterone and 17-hydroxypregnenolone to 17-hydroxyprogesterone, leading to reduced production of cortisol, aldosterone, and sex steroids. 

This deficiency manifests differently across genders; affected males often experience pseudohermaphroditism due to impaired androgen synthesis, showing incomplete masculinization of the external genitalia, while females may show normal differentiation or mild virilization. 

The disorder is categorized into three types: salt-wasting, non-salt-wasting, and non-classic. 

The salt-wasting type, the most severe, involves significant sodium loss, posing immediate life-threatening risks like dehydration and poor feeding. The non-salt-wasting type maintains enough hormone production for sodium reabsorption, and the non-classic type exhibits the mildest symptoms without salt wasting. 

Both males and females with this condition may face fertility challenges, and females can also experience irregular menstruation and excessive body hair from childhood or puberty. 

Prompt diagnosis and treatment are critical, especially for newborns with the salt-wasting form to prevent fatal outcomes.

17α-Hydroxylase/17,20-Lyase Deficiency  [16.]

17α-hydroxylase/17,20-lyase deficiency, a rare autosomal recessive form of congenital adrenal hyperplasia (CAH), is caused by mutations in the CYP17A1 gene. 

This deficiency leads to significantly reduced production of cortisol, estrogens, and androgens, resulting in an accumulation of mineralocorticoid precursors that cause symptoms like hypertension and hypokalemia. 

Patients may also experience sexual development issues including primary amenorrhea and sexual infantilism in genetically female individuals and ambiguous genitalia in genetically male individuals. Treatment typically involves glucocorticoid and sex steroid replacement to manage hormone levels and alleviate symptoms. 

The disorder is characterized by over 90 identified genetic mutations, varying in prevalence across different ethnic groups. A case highlighted in the study involves a 17-year-old female presenting with primary amenorrhea and lack of secondary sexual characteristics, who was treated with prednisolone and ethinyl estradiol.

P450 Oxidoreductase Deficiency  [9.] 

Cytochrome P450 oxidoreductase deficiency (PORD) is an autosomal recessive disorder that affects steroidogenesis, presenting a broad range of symptoms from cortisol deficiency and skeletal abnormalities to disorders of sex development (DSD).  

Patients may exhibit cortisol production but cannot adequately increase cortisol levels during stress, and might experience mild mineralocorticoid excess leading to hypertension in adulthood. 

PORD can cause ambiguous genitalia in both sexes, ovarian cysts in females, under-masculinization in males, and maternal virilization during pregnancy if the fetus is affected.

PORD shows impaired activity of enzymes like 17α-hydroxylase and 21-hydroxylase essential for cortisol, aldosterone, and sex steroid synthesis. Confirmatory molecular genetic testing identifies pathogenic variants in the POR gene.

Management includes glucocorticoid replacement for cortisol deficiency, surgical interventions for skeletal and genital abnormalities, and hormone therapies for sex steroid deficiencies. Monitoring and early intervention aim to manage developmental delays and prevent complications such as adrenal crisis.

Congenital Lipoid Adrenal Hyperplasia (StAR Deficiency)  [11.]

Lipoid congenital adrenal hyperplasia (lipoid CAH), the most severe form of CAH, is typically caused by mutations in the steroidogenic acute regulatory protein (STAR). These mutations disrupt the transfer of cholesterol within mitochondria, essential for synthesizing pregnenolone, the precursor of all steroid hormones.

 A study involving a Scandinavian infant with a salt-losing crisis revealed two de novo heterozygous mutations in the STAR gene, highlighting that lipoid CAH can arise from spontaneous mutations and is not limited to specific geographic regions.

This form of CAH is characterized by severe adrenal insufficiency from birth, often manifesting as a salt-losing crisis due to the inability to synthesize adequate mineralocorticoids and glucocorticoids.

Management of lipoid CAH requires prompt and aggressive treatment with glucocorticoid replacement to address cortisol deficiency and manage the salt-losing crisis. 

This case underscores the importance of considering lipoid CAH in the differential diagnosis of adrenal insufficiency in newborns, even in the absence of a family history, due to the possibility of de novo mutations.

Lab Testing for 17-Hydroxyprogesterone

Laboratory testing for 17-Hydroxyprogesterone plays a crucial role in diagnosing uncommon genetic disorder congenital adrenal hyperplasia.   

Testing for 17-Hydroxyprogesterone Levels, Sample Collection and Preparation

In adults, blood samples are typically collected from the patient via venipuncture, with serum or plasma separated from whole blood by centrifugation.  In newborns, sample collection is often done via venipuncture.  

Patients may be instructed to fast or avoid certain medications prior to sample collection to prevent potential interference with hormone levels.

Interpretation of Test Results

Reference Range for 17-Hydroxyprogesterone

Expected reference ranges vary widely depending on age, gender and, in premenopausal women, the timing of their cycle.  It is essential to contact the laboratory company used for their recommended reference ranges.  

One lab company reports reference ranges in adults as the following:  [1.]

Adult Male: 27−199 ng/dL

Adult Female:

• Follicular: 15−70 ng/dL
• Luteal: 35−290 ng/dL

Reference ranges for babies and children will differ depending on age and puberty. 

Optimal Levels of 17-Hydroxyprogesterone

 Because 17-OHP is primarily an intermediary hormone, an optimal range is generally considered anything within the reference range, provided the individual also has healthy levels of cortisol, aldosterone and androgens.  

Alterations in cortisol, aldosterone, and/or androgen levels should prompt a closer examination of 17-OHP levels, particularly if the individual is symptomatic.    

Clinical Significance of Elevated 17-Hydroxyprogesterone Levels

Elevated 17-OHP levels warrants immediate concern for and assessment of congenital adrenal hyperplasia, particularly in newborns.  

What Does Low 17-Hydroxyprogesterone Mean?

Low levels of 17-Hydroxyprogesterone can indicate underlying adrenal dysfunction or other endocrine disorders. 

Clinical Significance of Low 17-Hydroxyprogesterone Levels  [8.]

Low levels of 17-Hydroxyprogesterone may be indicative of adrenal insufficiency, a condition characterized by inadequate cortisol production.  

Low levels of 17-hydroxyprogesterone are often found in conditions where there is adrenal hypofunction or suppression of the pituitary-adrenal axis due to the therapeutic use of synthetic glucocorticoids. 

Essentially, low levels of 17-OHP may be caused by either primary adrenal insufficiency or conditions that impair ACTH production.

17-Hydroxyprogesterone Related Biomarkers to Test

Related biomarkers may be considered for a comprehensive assessment of adrenal function and hormonal balance.

Dehydroepiandrosterone-Sulfate (DHEA-S)

Dehydroepiandrosterone-sulfate, abbreviated as DHEA-S, is a steroid hormone primarily produced by the adrenal glands.  DHEA-S serves as a precursor to androgens and estrogens, playing a crucial role in the synthesis of sex hormones. 

Measuring DHEA-S levels alongside 17-Hydroxyprogesterone can provide additional information about adrenal function and adrenal and androgen hormone production.

Cortisol

Cortisol, often referred to as the "stress hormone," is another key biomarker of adrenal function.  Produced by the adrenal cortex, cortisol plays a central role in regulating metabolism, immune response, and stress adaptation. 

Cortisol levels are closely linked to those of 17-Hydroxyprogesterone, as both hormones are synthesized within the adrenal glands. 

Testosterone

Testosterone is the primary male sex hormone, although it is also present in lower concentrations in females. Produced by the testes in males and the ovaries in females, testosterone plays a vital role in reproductive function, muscle mass maintenance, and bone density regulation. 

Measurement of testosterone levels alongside 17-Hydroxyprogesterone can provide insights into androgenic hormone balance and adrenal androgen production.

Androstenedione

Testing androstenedione along with 17-hydroxyprogesterone may provide additional insight into adrenal and gonadal function, helping to diagnose conditions like congenital adrenal hyperplasia and assessing androgen levels. 

This combination aids in evaluating enzyme efficiency and hormonal pathways, crucial for understanding steroid metabolism.

ACTH

ACTH levels can be elevated in CAH due to decreased cortisol production; concern for CAH may warrant ACTH testing. 

Other Biomarkers to Consider

Additionally, practitioners may consider testing levels of other sex steroid hormones including estrogens, progesterone, as well as the mineralocorticoid aldosterone.  

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