Gonadal Hormones

The gonadal hormones are produced by the human gonads: the testes and the ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries. The primary hormones produced by these organs include androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens, 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 Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Menstrual Cycle and progesterone are the primary female hormones, which are responsible for egg development, the menstrual cycle Menstrual cycle The menstrual cycle is the cyclic pattern of hormonal and tissular activity that prepares a suitable uterine environment for the fertilization and implantation of an ovum. The menstrual cycle involves both an endometrial and ovarian cycle that are dependent on one another for proper functioning. There are 2 phases of the ovarian cycle and 3 phases of the endometrial cycle. Menstrual Cycle, and breast development. The gonadal hormones are part of the hypothalamic-pituitary-gonadal (HPG) axis and are regulated by the pituitary hormones Pituitary hormones The hypothalamic and pituitary hormones are the most important regulators of the endocrine system. The hypothalamus functions as the coordinating center between the CNS and endocrine system by integrating the signals received from the rest of the brain and releasing appropriate regulatory hormones to the pituitary gland. The pituitary gland then releases its own hormones in response to hypothalamic stimulation. Hypothalamic and 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 Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Gonadal hormones:

The gonadal hormones are produced by the human gonads: the testes and ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). 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 Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries that produce higher amounts of estrogens than androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
  • “Male” will be used to describe:
    • Androgenic hormones
    • Individuals with testes that produce higher amounts of androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens than estrogens

Hypothalamic-pituitary-gonadal (HPG) axis

Hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview 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 Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Menstrual Cycle
      • Progesterone
    • An LH surge triggers ovulation in females.
  • GnRH and FSH/LH secretions regulated by:
    • Hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview 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 Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Menstrual Cycle (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 Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview can freely cross cell membranes to bind to intracellular receptors.
  • Once bound to receptors → translocation to the nucleus
  • Hormone–receptor complex can bind DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure 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 Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. 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 Protein kinase A A group of enzymes that are dependent on cyclic amp and catalyze the phosphorylation of serine or threonine residues on proteins. Included under this category are two cyclic-amp-dependent protein kinase subtypes, each of which is defined by its subunit composition. Glycogen Metabolism

Image by Lecturio.

Effects of testosterone and other androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens

Testosterone, and other androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens, 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin becomes darker and thicker
      • ↑ Sebum secretion → can lead to acne
      • ↑ Apocrine sweat glands
    • Growth of the larynx Larynx The larynx, also commonly called the voice box, is a cylindrical space located in the neck at the level of the C3-C6 vertebrae. The major structures forming the framework of the larynx are the thyroid cartilage, cricoid cartilage, and epiglottis. The larynx serves to produce sound (phonation), conducts air to the trachea, and prevents large molecules from reaching the lungs. Larynx → deepening of the voice
  • Musculoskeletal effects:
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones growth
    • ↑ Muscle mass
    • Connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. 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 Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. 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 Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. 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 Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries to produce:
    • Estrogens:
      • E2: primary estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries produced in reproductive-aged females
      • E1: weaker estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries; primary estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries in menopausal females
      • Estriol (E3): primarily produced in pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
    • 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 Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. 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 Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus and pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. 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 Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty → reproductive years → menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause)
  • Circadian rhythms: 24-hour cycles
  • Ultradian rhythms: < 24-hour cycles
  • Infradian rhythms: > 24-hour cycles (monthly rhythms)
Changes in pulsatile secretion of fsh and lh

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 Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland occurs in response to the pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. 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 Menstrual cycle The menstrual cycle is the cyclic pattern of hormonal and tissular activity that prepares a suitable uterine environment for the fertilization and implantation of an ovum. The menstrual cycle involves both an endometrial and ovarian cycle that are dependent on one another for proper functioning. There are 2 phases of the ovarian cycle and 3 phases of the endometrial cycle. 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 Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Menstrual Cycle and progesterone synthesis

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

  • Key enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in the pathway:
    • 17α-hydroxylase: converts progesterone to 17α-OHP
    • Aromatase: converts androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens 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
Synthesis of estrogen and testosterone

Synthesis of estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries 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 Menstrual cycle The menstrual cycle is the cyclic pattern of hormonal and tissular activity that prepares a suitable uterine environment for the fertilization and implantation of an ovum. The menstrual cycle involves both an endometrial and ovarian cycle that are dependent on one another for proper functioning. There are 2 phases of the ovarian cycle and 3 phases of the endometrial cycle. 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 Menstrual cycle The menstrual cycle is the cyclic pattern of hormonal and tissular activity that prepares a suitable uterine environment for the fertilization and implantation of an ovum. The menstrual cycle involves both an endometrial and ovarian cycle that are dependent on one another for proper functioning. There are 2 phases of the ovarian cycle and 3 phases of the endometrial cycle. Menstrual Cycle
    • Myometrial growth
    • ↑ Strength/integrity of vaginal tissue
    • ↑ Vaginal lubrication
    • ↑ Ovarian growth
  • Breasts Breasts The breasts are found on the anterior thoracic wall and consist of mammary glands surrounded by connective tissue. The mammary glands are modified apocrine sweat glands that produce milk, which serves as nutrition for infants. Breasts are rudimentary and usually nonfunctioning in men. Breasts:
    • Stimulates breast development
    • ↓ Milk production
  • Produces the “female physique” owing to fat deposition in: 
    • Breasts Breasts The breasts are found on the anterior thoracic wall and consist of mammary glands surrounded by connective tissue. The mammary glands are modified apocrine sweat glands that produce milk, which serves as nutrition for infants. Breasts are rudimentary and usually nonfunctioning in men. 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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones effects:
    • Promotes bone growth:
      • Triggers growth spurt at puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty
      • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis becomes a problem when ↓ E2 in menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. 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 Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause, ↓ E2 → ↑ cardiovascular risk 
  • ↑ Clotting factors → thromboembolic risks are the primary major risk of estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries 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 Menstrual cycle The menstrual cycle is the cyclic pattern of hormonal and tissular activity that prepares a suitable uterine environment for the fertilization and implantation of an ovum. The menstrual cycle involves both an endometrial and ovarian cycle that are dependent on one another for proper functioning. There are 2 phases of the ovarian cycle and 3 phases of the endometrial cycle. Menstrual Cycle → prepares the endometrium for implantation Implantation Endometrial implantation of embryo, mammalian at the blastocyst stage. Fertilization and First Week
    • ↑ Cervical mucus production → required for sperm transport into the uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Posterior Abdominal Wall
    • Progestin withdrawal triggers menstrual bleeding.
  • Breast effects:
    • ↑ Milk glands → can cause breast tenderness leading up to menses Menses The periodic shedding of the endometrium and associated menstrual bleeding in the menstrual cycle of humans and primates. Menstruation is due to the decline in circulating progesterone, and occurs at the late luteal phase when luteolysis of the corpus luteum takes place. Menstrual Cycle
    • ↓ Milk production → suppresses lactation during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • ↑ Basal body temperature → can be used to track ovulation
  • Required for the development of the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care

Comparison Summary: Male versus Female

Table: Comparison of female and male structures and hormones
Female Male
Ovary Gonad Testis
Ova Germ cells Spermatozoa
Follicle Enclosure Seminiferous tubule
Granulosa cells Adjacent cells Sertoli cells
  • Estradiol Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Menstrual Cycle
  • Progesterone
  • Inhibin
  • Activin
Adjacent cell products
  • Estradiol Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Menstrual Cycle
  • Inhibin
  • Androgen-binding protein (ABP)
  • Growth factors
Theca cells Interstitium Leydig cells
  • Testosterone
  • Androgens
  • Progesterone
Interstitial products Testosterone
Table: Comparison between estrogens and androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens
Organ system Estrogens Androgens
Reproductive organs
  • ↑ Growth and development of:
    • Endometrium
    • Myometrium
    • Vagina
    • Ovaries
  • ↑ Cervical and vaginal secretions
  • → ↑ Vaginal lubrication
  • ↑ Spermatogenesis
  • ↑ Growth and development of:
    • Testes
    • Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands
    • Seminal vesicles Seminal vesicles A saclike, glandular diverticulum on each ductus deferens in male vertebrates. It is united with the excretory duct and serves for temporary storage of semen. Prostate and other Male Reproductive Glands
    • Penis Penis The penis is the male organ of copulation and micturition. The organ is composed of a root, body, and glans. The root is attached to the pubic bone by the crura penis. The body consists of the 2 parallel corpora cavernosa and the corpus spongiosum. The glans is ensheathed by the prepuce or foreskin. 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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones growth
  • Closes growth plates
  • Hips widen
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones growth
  • ↑ Muscle mass
  • Connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. 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 Larynx The larynx, also commonly called the voice box, is a cylindrical space located in the neck at the level of the C3-C6 vertebrae. The major structures forming the framework of the larynx are the thyroid cartilage, cricoid cartilage, and epiglottis. The larynx serves to produce sound (phonation), conducts air to the trachea, and prevents large molecules from reaching the lungs. Larynx → deepening of the voice
  • Erythropoiesis Erythropoiesis Erythropoiesis starts with hematopoietic stem cells, which develop into lineage-committed progenitors and differentiate into mature RBCs. The process occurs in stages, and extrusion of the nuclei and organelles occurs prior to maturation. Thus, mature RBCs lack nuclei and have a biconcave shape. Erythrocytes
  • ↑ Steroid-binding proteins

Clinical Relevance

  • Hormonal contraceptives Hormonal contraceptives Hormonal contraceptives (HCs) contain synthetic analogs of the reproductive hormones estrogen and progesterone, which may be used either in combination or in progestin-only formulations for contraception. 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 Hormonal contraceptives Hormonal contraceptives (HCs) contain synthetic analogs of the reproductive hormones estrogen and progesterone, which may be used either in combination or in progestin-only formulations for contraception. 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 Hormone Replacement Therapy Estrogen and progesterone are the sex hormones produced by the ovaries in premenopausal women. They are used to treat hypogonadism (primary ovarian insufficiency), menopausal symptoms, and gender dysphoria in transgender women. Noncontraceptive Estrogen and Progestins (HRT): typically given as “bioidentical” estradiol and progesterone because of improved safety profiles. Hormone replacement therapy Hormone Replacement Therapy Estrogen and progesterone are the sex hormones produced by the ovaries in premenopausal women. They are used to treat hypogonadism (primary ovarian insufficiency), menopausal symptoms, and gender dysphoria in transgender women. Noncontraceptive Estrogen and Progestins is indicated in individuals suffering from symptoms caused by hormone fluctuations and dropping hormone levels in menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause (e.g., hot flashes, mood swings). Other indications include primary ovarian insufficiency Primary ovarian insufficiency Primary ovarian insufficiency (POI) is a condition resulting from the depletion or dysfunction of the ovarian follicles, leading to cessation of ovulation and menses before age 40. Primary ovarian insufficiency is primarily idiopathic. Patients present with signs and symptoms of menopause prior to age 40, including oligo- or amenorrhea, vaginal dryness (often leading to dyspareunia), and infertility. Primary Ovarian Insufficiency (i.e., premature menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause), male hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism, and gender dysphoria Gender dysphoria Gender dysphoria, formerly known as gender identity disorder, is the emotional discomfort felt by a patient because of the incongruence between their experienced gender and the gender they were assigned at birth (continuous inner conflict between gender identity and sexual identity). Gender Dysphoria.
  • Hypogonadism: condition characterized by reduced or absent sex hormone production by the testes or ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries. Hypogonadism may be due to failure of the gonads or defects in hypothalamic or pituitary stimulatory secretions. Findings include infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility, increased risk of osteoporosis, erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. 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 Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause, with cessation of ovulation and menses Menses The periodic shedding of the endometrium and associated menstrual bleeding in the menstrual cycle of humans and primates. Menstruation is due to the decline in circulating progesterone, and occurs at the late luteal phase when luteolysis of the corpus luteum takes place. Menstrual Cycle 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 Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia: benign proliferation of male breast glandular and ductal tissue. Causes may be physiologic (due to imbalances in estrogens and androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens that occur most commonly in neonates, puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty, and older men) or may be due to medications, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease, hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism, hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism, starvation, and testicular neoplasms. When present in men, it must be differentiated from breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. 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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