Gonadal Hormones

The gonadal hormones are produced by the human gonads: the testes and the ovaries. The primary hormones produced by these organs include androgens, estrogens, and progestins. Testosterone is the primary androgen, and it plays a critical role in the development of the primary and secondary male sex characteristics as well as of spermatogenesis. Estradiol and progesterone are the primary female hormones, which are responsible for egg development, the menstrual cycle, and breast development. The gonadal hormones are part of the hypothalamic-pituitary-gonadal (HPG) axis and are regulated by the pituitary hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In turn, FSH and LH are both regulated by gonadotropin-releasing hormone (GnRH) secreted from the hypothalamus.

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Overview

Definition

Gonadal hormones:

The gonadal hormones are produced by the human gonads: the testes and ovaries. These hormones include:

  • Androgens, including testosterone
  • Estrogens
  • Progestins

Gendered terminology:

Recognizing the complexity and sensitive nature around gendered terminology, for the purposes of this document:

  • The authors recognize that there is a spectrum (rather than a binary division) of gender identities, sexual organs, and secondary sex characteristics.
  • “Female” will be used to describe:
    • Estrogenic hormones
    • Individuals with ovaries that produce higher amounts of estrogens than androgens
  • “Male” will be used to describe:
    • Androgenic hormones
    • Individuals with testes that produce higher amounts of androgens than estrogens

Hypothalamic-pituitary-gonadal (HPG) axis

Hormones secreted by the gonads are stimulated by, and help to regulate, the hypothalamic-pituitary-testicular (HPT) axis in males and the hypothalamic-pituitary-ovarian (HPO) axis in females.

  • Hypothalamus:
    • Secretes gonadotropin-releasing hormone (GnRH) 
    • Gonadotropin-releasing hormone is secreted by the preoptic nuclei (primary) and supraoptic nuclei.
  • Pituitary:
    • Gonadotropin-releasing hormone stimulates the gonadotropic cells to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
    • FSH: stimulates development of the gametes
    • LH: stimulates androgen production in both sexes
  • Gonads:
    • Produce all gonadal hormones:
      • Testosterone
      • Estradiol
      • Progesterone
    • An LH surge triggers ovulation in females.
  • GnRH and FSH/LH secretions regulated by:
    • Hormones produced from the gonads
    • Stress (especially chronic malnourishment and overexercise)

Sex hormone synthesis pathway

All of the gonadal hormones are produced from cholesterol via a series of enzymatic steps. The steps in the sex hormone metabolic pathway include:

  • Cholesterol → 
  • Pregnenolone → 
  • Progesterone → 
  • 17α-hydroxyprogesterone (17α-OHP) → 
  • Androstenedione, which can be converted into either → 
  • Testosterone or estrone (E1), both of which can be converted into → 
  • Estradiol (E2)

Transport of gonadal hormones within the blood

Gonadal hormones are lipophilic, so they must be protein-bound to travel in the blood. In general, they are bound to:

  • Sex hormone–binding globulin (SHBG): approximately 38%–44%
  • Other proteins (primarily albumin and corticosteroid-binding globulin): approximately 54%–60%
  • Free hormone (the only biologically active form): approximately 2%

Gonadal hormone receptors

  • Hormones can freely cross cell membranes to bind to intracellular receptors.
  • Once bound to receptors → translocation to the nucleus
  • Hormone–receptor complex can bind DNA and affect gene expression
Diagram depicting effects of gonadal hormones

Diagram depicting how gonadal hormones exert their effects on cells.
DHT: dihydrotestosterone

Image by Lecturio.

Male Reproductive Endocrinology

Hypothalamic-pituitary-testicular axis overview

  • Preoptic neurons in the hypothalamus secrete GnRH. 
  • GnRH stimulates the anterior pituitary to release:
    • LH
    • FSH
  • LH and FSH stimulate cells in the testes:
    • LH: primarily affects the testicular Leydig cells → stimulates the production of testosterone
    • FSH: primarily affects the testicular Sertoli cells → stimulates spermatogenesis and production of inhibin
  • Some testosterone is converted in peripheral cells to:
    • Dihydrotestosterone (DHT)
    • 17-ketosteroids
  • Feedback and regulation of the HPT axis:
    • Testosterone: inhibits secretion of GnRH, FSH, and LH
    • Inhibin: selectively inhibits FSH
Hypothalamic-Pituitary-Testes Axis

Hypothalamic-pituitary-testicular axis
FSH: follicle-stimulating hormone
GnRH: gonadotropin-releasing hormone
LH: luteinizing hormone

Image by Lecturio.

Sex cord-stromal cells

  • Sperm develop within the seminiferous tubules of the testes
  • The tubules include 2 primary sex cord-stromal cells:
    • Sertoli cells (inner lining of the tubules): 
      • Responsible for spermatogenesis
      • Contain aromatase: some testosterone is converted to E2
    • Leydig cells: synthesize testosterone

Effects of luteinizing hormone and follicle-stimulating hormone on the testes

  • LH:
    • Activates side-cleaving enzyme within Leydig cells, which starts the conversion of cholesterol to testosterone
    • Testosterone accumulates in the Leydig cells → moves to both:
      • Neighboring Sertoli cells 
      • Blood for transport throughout the body
  • FSH: 
    • Stimulates spermatogenesis within Sertoli cells
    • Spermatogenesis requires testosterone produced by the Leydig cells.
Actions of LH and FSH on the testes

Actions of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) on the testes
ABP: androgen-binding protein
PKA: protein kinase A

Image by Lecturio.

Effects of testosterone and other androgens

Testosterone, and other androgens, are responsible for the development of both primary and secondary male sex characteristics. 

  • Stimulates growth of the male reproductive organs:
    • Enlargement of the testes and scrotum
    • Duct and glandular development of the male reproductive system
  • Stimulates spermatogenesis; without testosterone, males become sterile
  • Stimulates the development of secondary sex characteristics:
    • Androgenic hair: 
      • Pubic hair
      • Axillary hair
      • Facial hair (beard and mustache regions)
    • Dermatologic changes: 
      • Skin becomes darker and thicker
      • ↑ Sebum secretion → can lead to acne
      • ↑ Apocrine sweat glands
    • Growth of the larynx → deepening of the voice
  • Musculoskeletal effects:
    • ↑ Bone growth
    • ↑ Muscle mass
    • ↑ Connective tissue

Secretion of testosterone across the male life span

Testosterone secretion varies throughout the male life span:

  • Peak levels:
    • In utero
    • Starting at puberty throughout adult life
  • Begins dropping around age 60
  • Testosterone is secreted in pulses throughout the day.
Average testosterone concentrations

Average testosterone concentrations over a life span

Image by Lecturio.

Female Reproductive Endocrinology

Hypothalamic-pituitary-ovarian axis overview

  • Preoptic neurons in the hypothalamus secrete GnRH in a pulsatile fashion.
  • GnRH pulses, along with other biologic rhythms, trigger the anterior pituitary to release:
    • FSH
    • LH
  • FSH and LH stimulate the ovaries to produce:
    • Estrogens:
      • E2: primary estrogen produced in reproductive-aged females
      • E1: weaker estrogen; primary estrogen in menopausal females
      • Estriol (E3): primarily produced in pregnancy
    • Progestins (only produced in significant quantities after ovulation):
      • Progesterone
      • Progesterone-like compounds (e.g., 17α-OHP)
    • Inhibins
    • Activins
  • Feedback and regulation of the HPO axis:
    • Estrogens and progesterone inhibit:
      • Pituitary secretion of FSH and LH
      • Hypothalamic secretion of GnRH
      • Exception: For a short time midcycle, estrogens sensitize the pituitary and hypothalamus and function as a positive feedback mechanism, leading up to the LH surge with ovulation.
    • Inhibin: selectively inhibits FSH secretion
    • Activin: stimulates LH secretion, especially midcycle
Hypothalamic pituitary ovarian axis

Positive and negative feedback loops of the hypothalamic-pituitary-ovarian axis:
Note that estrogens and progestins have both a positive and a negative influence on the hypothalamus and pituitary gland, depending on the phase of the cycle. Estrogens provide negative feedback until the midpoint of the cycle, when it becomes positive and provides sensitization for the gonadotropes right before the luteinizing hormone (LH) surge.
FSH: follicle-stimulating hormone
GnRH: gonadotropin-releasing hormone

Image by Lecturio.

Gonadotropin Pulsatility

Gonadotropin-releasing hormone is released in a pulsatile fashion, following multiple biologic rhythms:

  • Major stages of growth and development (e.g., childhood → puberty → reproductive years → menopause)
  • Circadian rhythms: 24-hour cycles
  • Ultradian rhythms: < 24-hour cycles
  • Infradian rhythms: > 24-hour cycles (monthly rhythms)
Gonadal Hormones

Changes in pulsatile secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) throughout the day and across the span of a female’s life:
Pulsatile release of FSH and LH from the pituitary gland occurs in response to the pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus.

Image by Lecturio.

Structure of developing follicles

  • The developing follicle is a small cyst that forms around each oocyte.
  • Surrounded by 2 primary stromal cells:
    • Granulosa cells
    • Theca cells
  • The stromal cells produce the gonadal hormones in females.
Structure of primary ovarian follicle

Structure of a primary ovarian follicle

Image by Lecturio.

Follicle-stimulating hormone and luteinizing hormone

  • Functions of FSH:
    • Stimulates follicular development and egg maturation
    • Stimulates the granulosa cells within the ovary to produce estradiol
  • Functions of LH:
    • A surge of LH mid–menstrual cycle triggers ovulation.
    • Stimulates theca cells within the ovary to produce testosterone (most of which is converted to E2 in the granulosa cells).

Estradiol and progesterone synthesis

Review of the sex hormone metabolic pathway: cholesterol → pregnenolone → progesterone → 17α-OHP → androstenedione → testosterone or E1 → E2

  • Key enzymes in the pathway:
    • 17α-hydroxylase: converts progesterone to 17α-OHP
    • Aromatase: converts androgens to estrogens
      • Converts androstenedione to E1
      • Converts testosterone to E2
  • Within theca cells:
    • Contains 17α-hydroxylase but not aromatase
    • Cholesterol → testosterone (stimulated by LH)
    • No aromatase: theca cells are unable to convert testosterone to estradiol
  • Within granulosa cells:
    • Contains aromatase, but not 17α-hydroxylase
    • Cholesterol is converted to progesterone
    • No 17α-hydroxylase: granulosa cells are unable to convert progesterone to 17α-OHP
    • Testosterone generated from neighboring theca cells → converted to E2 by aromatase within the granulosa cells (stimulated by FSH)
  • End results:
    • Theca cells produce testosterone (most, but not all of which, is converted to E2)
    • Granulosa cells produce:
      • E2
      • Progesterone
Gonadal Hormones

Synthesis of estrogen and testosterone in the ovary
AC: adenylyl cyclase
17β-HSD: 17β-hydroxysteroid dehydrogenase

Image by Lecturio.

Effects of estrogens

Estrogens play a major role in the sexual development of females and the menstrual cycle; however, there are numerous nonreproductive functions of estrogens as well.

  • Stimulate growth of the female reproductive organs:
    • Responsible for the buildup of endometrial lining each month during the menstrual cycle
    • Myometrial growth
    • ↑ Strength/integrity of vaginal tissue
    • ↑ Vaginal lubrication
    • ↑ Ovarian growth
  • Breasts:
    • Stimulates breast development
    • ↓ Milk production
  • Produces the “female physique” owing to fat deposition in: 
    • Breasts
    • Hips, buttocks, and thighs
    • Labia majora and mons pubis
  • Endocrine effects:
    • Inhibit FSH and GnRH → estrogens are effective contraceptive agents
    • ↑ LH receptors on granulosa cells
  • Bone effects:
    • Promotes bone growth:
      • Triggers growth spurt at puberty
      • Osteoporosis becomes a problem when ↓ E2 in menopause
    • Closes growth plates
  • Favorable effects on lipid profiles
    • ↓ Total cholesterol and LDL
    • ↑ HDL
    • Clinical relevance: 
      • Premenopausal women have ↓ cardiovascular risk as compared with men of the same age
      • At menopause, ↓ E2 → ↑ cardiovascular risk 
  • ↑ Clotting factors → thromboembolic risks are the primary major risk of estrogen therapies

Effects of progestins

Progesterone is primarily produced by the corpus luteum after ovulation. 

  • Uterine effects:
    • ↑ Endometrial secretions
    • Stabilizes and causes maturation of the endometrium in the 2nd half of the menstrual cycle → prepares the endometrium for implantation
    • ↑ Cervical mucus production → required for sperm transport into the uterus
    • Progestin withdrawal triggers menstrual bleeding.
  • Breast effects:
    • ↑ Milk glands → can cause breast tenderness leading up to menses
    • ↓ Milk production → suppresses lactation during pregnancy
  • ↑ Basal body temperature → can be used to track ovulation
  • Required for the development of the placenta during pregnancy

Comparison Summary: Male versus Female

Table: Comparison of female and male structures and hormones
FemaleMale
OvaryGonadTestis
OvaGerm cellsSpermatozoa
FollicleEnclosureSeminiferous tubule
Granulosa cellsAdjacent cellsSertoli cells
  • Estradiol
  • Progesterone
  • Inhibin
  • Activin
Adjacent cell products
  • Estradiol
  • Inhibin
  • Androgen-binding protein (ABP)
  • Growth factors
Theca cellsInterstitiumLeydig cells
  • Testosterone
  • Androgens
  • Progesterone
Interstitial productsTestosterone
Table: Comparison between estrogens and androgens
Organ systemEstrogensAndrogens
Reproductive organs
  • ↑ Growth and development of:
    • Endometrium
    • Myometrium
    • Vagina
    • Ovaries
  • ↑ Cervical and vaginal secretions
  • → ↑ Vaginal lubrication
  • ↑ Spermatogenesis
  • ↑ Growth and development of:
    • Testes
    • Prostate
    • Seminal vesicles
    • Penis
    • Clitoris in females
  • ↑ Libido
Dermatologic effects (in all people)Mild thickening of the skin
  • ↑ Growth of:
    • Facial hair
    • Axillary and pubic hair
  • ↑ Sebaceous secretions → ↑ acne
  • Thickening and darkening of the skin
Musculoskeletal effects
  • ↑ Bone growth
  • Closes growth plates
  • Hips widen
  • ↑ Bone growth
  • ↑ Muscle mass
  • ↑ Connective tissue
Other effects
  • Breast development
  • Fat deposits:
    • Labia majora and mons pubis
    • Hips, buttocks, and thighs
  • ↑ Clotting factors
  • ↑ Steroid-binding proteins
  • Favorable effects on lipid profile:
    • ↓ Total and LDL
    • ↑ HDL
  • ↑ Growth of larynx → deepening of the voice
  • ↑ Erythropoiesis
  • ↑ Steroid-binding proteins

Clinical Relevance

  • Hormonal contraceptives: contain either a combination of ethinyl estradiol and progestin or progestin alone. These synthetic hormones carry slightly higher cardiovascular risks than estradiol and progesterone but have better contraceptive effects. Hormonal contraceptives are available in many forms (e.g., pills, intrauterine devices). They work by inhibiting FSH release (preventing follicular development), and the progestins also suppress endometrial development and cervical mucus production.
  • Hormone replacement therapy (HRT): typically given as “bioidentical” estradiol and progesterone because of improved safety profiles. Hormone replacement therapy is indicated in individuals suffering from symptoms caused by hormone fluctuations and dropping hormone levels in menopause (e.g., hot flashes, mood swings). Other indications include primary ovarian insufficiency (i.e., premature menopause), male hypogonadism, and gender dysphoria.
  • Hypogonadism: condition characterized by reduced or absent sex hormone production by the testes or ovaries. Hypogonadism may be due to failure of the gonads or defects in hypothalamic or pituitary stimulatory secretions. Findings include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Diagnosis requires assessment of the history, physical exam, and labs. Management is with hormone replacement therapy.
  • Primary ovarian insufficiency (POI): Previously referred to as “premature ovarian failure,” POI describes cases of early menopause, with cessation of ovulation and menses prior to age 40. Management requires HRT to prevent early osteoporosis and cardiovascular disease. Fertility concerns must also be addressed as desired by the individual.
  • Gynecomastia: benign proliferation of male breast glandular and ductal tissue. Causes may be physiologic (due to imbalances in estrogens and androgens that occur most commonly in neonates, puberty, and older men) or may be due to medications, cirrhosis, CKD, hypogonadism, hyperthyroidism, starvation, and testicular neoplasms. When present in men, it must be differentiated from breast cancer.

References

  1. Saladin, K.S., Miller, L. (2004). Anatomy and Physiology, 3rd ed., pp. 1030–1032, 1058–1060. 
  2. Rosner, J. (2020). Physiology, female reproduction. StatPearls. Retrieved August 3, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/771/ 
  3. Gurung, P. (2021). Physiology, male reproductive system. StatPearls. Retrieved August 3, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/770/ 
  4. Braunstein, G.D., Anawalt, B.D. (2021). Management of gynecomastia. UpToDate. Retrieved August 3, 2021, from https://www.uptodate.com/contents/management-of-gynecomastia 
  5. Welt, C.K. (2020). Management of spontaneous primary ovarian insufficiency (premature ovarian failure). UpToDate. Retrieved August 3, 2021, from https://www.uptodate.com/contents/management-of-spontaneous-primary-ovarian-insufficiency-premature-ovarian-failure

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