What Is 17β-Hydroxysteroid dehydrogenase II

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Last updated: April 14, 2026

Quick Answer: 17β-Hydroxysteroid dehydrogenase type II (HSD17B2) is an enzyme encoded by the HSD17B2 gene in humans, primarily responsible for inactivating potent sex hormones like estradiol and testosterone by converting them into less active forms. It is highly expressed in the placenta, liver, and small intestine. Mutations in this enzyme are linked to hormonal imbalances and disorders such as endometriosis and prostate cancer.

Key Facts

17β-HSD2 is encoded by the HSD17B2 gene located on chromosome 16q22.1
It inactivates estradiol by converting it to estrone with a catalytic efficiency of ~3.5 × 10^5 M⁻¹s⁻¹
The enzyme is highly expressed in the human placenta during the third trimester of pregnancy
HSD17B2 expression decreases by up to 70% in endometriotic tissue compared to normal endometrium
It also converts active testosterone into androstenedione, reducing androgen activity in target tissues

Overview

17β-Hydroxysteroid dehydrogenase type II (HSD17B2) is a critical enzyme involved in steroid hormone metabolism, particularly in regulating the levels of active sex hormones. It belongs to a family of 15 known hydroxysteroid dehydrogenases and plays a key role in maintaining hormonal balance by inactivating potent steroids.

Primarily expressed in epithelial tissues such as the placenta, small intestine, and liver, HSD17B2 ensures that high concentrations of active hormones like estradiol and testosterone do not accumulate in sensitive tissues. Its activity is essential during pregnancy and in protecting tissues from excessive hormonal stimulation.

Location: The HSD17B2 gene is located on chromosome 16q22.1, a region associated with several endocrine-related disorders and cancers.
Function: It catalyzes the oxidation of estradiol to estrone and testosterone to androstenedione, reducing their biological potency.
Tissue expression: Highest levels are found in the placenta during the third trimester, where it protects the fetus from maternal estrogen overload.
Enzyme class: It is a NAD+-dependent dehydrogenase, distinguishing it from other isoforms that use NADPH for reductive activity.
Regulation: Expression is upregulated by progestins and glucocorticoids and suppressed by inflammatory cytokines like IL-1β and TNF-α.

How It Works

The enzyme operates through a precise biochemical mechanism involving cofactor binding and substrate specificity. Its dehydrogenase activity ensures hormonal homeostasis in multiple organ systems.

Substrate specificity: Preferentially converts estradiol (E2) to estrone (E1) with a Km of approximately 20 nM, making it highly efficient at low hormone concentrations.
Cofactor requirement: Requires NAD+ as a cofactor, unlike type I 17β-HSD, which uses NADPH to perform the reverse reaction.
Reaction rate: Exhibits a catalytic efficiency (kcat/Km) of 3.5 × 10^5 M⁻¹s⁻¹ for estradiol, indicating rapid inactivation under physiological conditions.
pH optimum: Functions optimally at a pH of 9.0, which is unusual for intracellular enzymes but consistent with its localization in alkaline microenvironments.
Membrane association: Anchored to the endoplasmic reticulum membrane, allowing it to regulate steroid flux between cellular compartments.
Inhibitors: Sensitive to flufenamic acid and other nonsteroidal anti-inflammatory drugs, which can reduce its activity by up to 60% in vitro.

Key Comparison

Property	HSD17B2 (Type II)	HSD17B1 (Type I)	HSD17B3 (Type III)
Primary Function	Inactivates estradiol and testosterone	Activates estrone to estradiol	Converts androstenedione to testosterone
Reaction Direction	Oxidative (uses NAD+)	Reductive (uses NADPH)	Reductive (uses NADPH)
Main Tissue Expression	Placenta, liver, intestine	Ovaries, placenta, breast	Testes, adrenal glands
pH Optimum	9.0	6.0	7.5
Clinical Relevance	Endometriosis, prostate cancer	Breast cancer progression	Androgen insensitivity disorders

This comparison highlights the functional diversity within the 17β-HSD family. While HSD17B2 acts as a protective enzyme by reducing hormone activity, others like HSD17B1 amplify hormonal signals, underscoring the balance required in steroid metabolism.

Key Facts

Understanding the biochemical and physiological role of HSD17B2 provides insight into its importance in health and disease. Its expression patterns and regulatory mechanisms are well-documented in clinical studies.

Gene length: The HSD17B2 gene spans approximately 18 kilobases and contains 10 exons, as confirmed by genomic sequencing in 1993.
Pregnancy role: Placental expression increases fivefold between the second and third trimesters, peaking at term to protect fetal development.
Disease link: Reduced HSD17B2 levels are found in 70–80% of endometriosis cases, contributing to local estrogen excess.
Cancer relevance: In prostate cancer, loss of HSD17B2 expression correlates with higher tumor grade and androgen sensitivity.
Epigenetic regulation: Promoter methylation silences HSD17B2 in 40% of colorectal cancer samples, suggesting a tumor-suppressor role.
Species conservation: The enzyme shares 88% amino acid homology between humans and mice, indicating strong evolutionary conservation.

Why It Matters

17β-Hydroxysteroid dehydrogenase type II is more than a metabolic enzyme—it is a gatekeeper of hormonal balance with far-reaching implications in reproductive health and cancer biology. Its dysfunction can lead to pathological conditions driven by unregulated steroid exposure.

Endometriosis: Low HSD17B2 activity allows estradiol accumulation in ectopic tissue, promoting lesion growth and inflammation.
Fetal protection: In the placenta, it prevents maternal estrogen from crossing into fetal circulation, avoiding developmental disruption.
Liver detoxification: Contributes to the first-pass metabolism of sex hormones, reducing systemic hormone load.
Drug interactions: NSAIDs like flufenamic acid may inhibit HSD17B2, potentially altering hormone levels during chronic use.
Therapeutic target: Restoring HSD17B2 expression is being explored as a novel treatment strategy for estrogen-dependent cancers.

Given its pivotal role in hormone regulation, continued research into HSD17B2 offers promising avenues for diagnosing and treating endocrine disorders, cancers, and fertility issues. Understanding its function enhances our ability to modulate steroid pathways safely and effectively.