Ovarian Hormones and Control of Ovarian Functions

Introduction

The ovaries function as both reproductive and endocrine organs, producing hormones that regulate female sexual development, menstrual cyclicity, fertility, and pregnancy. Their activities are precisely coordinated through interactions among the ovaries, hypothalamus, and pituitary gland.

Ovarian Hormones

The ovaries secrete four major hormones: estrogens, progesterone, inhibins, and relaxin.

Estrogens

• The principal naturally occurring estrogens are 17β-estradiol, estrone, and estriol.
• Among these, 17β-estradiol is the most biologically active estrogen.
• Estradiol is approximately 10–20 times more potent than estrone and about 80 times more potent than estriol.

H4: Source

• Estrogens are produced mainly by the granulosa cells of developing ovarian follicles.
• Additional estrogen is secreted by the corpus luteum after ovulation.
• During pregnancy, large amounts of estrogen are synthesized by the placenta.
• The adrenal cortex does not secrete estrogen directly. However, adrenal androgens can be converted to estrogens in peripheral tissues by the enzyme aromatase.

Synthesis

• Estrogens are steroid hormones synthesized from cholesterol.
• In the theca interna cells, luteinizing hormone stimulates the formation of androgen precursors, mainly androstenedione and testosterone.
• These androgens diffuse into granulosa cells.
• Follicle-stimulating hormone enhances aromatase activity in granulosa cells, leading to conversion of androgens into estrogens.
• In mature follicles, granulosa cells also acquire receptors for luteinizing hormone, which further supports estrogen production.

Secretion

• Estrogen secretion shows two peaks during the menstrual cycle.
• The larger peak occurs just before ovulation during the late follicular phase.
• A smaller peak occurs during the mid-luteal phase.
• Estrogen secretion declines markedly after menopause because of loss of ovarian follicular activity.

Metabolism

• About 98% of circulating estrogen is bound to plasma proteins.
• Approximately 60% is bound to albumin, while about 38% is bound to sex hormone-binding globulin.
• Only a small free fraction circulates in plasma and is biologically active.
• Estrogens are metabolized primarily in the liver.
• Hepatic metabolism involves oxidation and conversion into glucuronide and sulfate conjugates.
• These water-soluble metabolites are excreted mainly in urine, with smaller amounts eliminated in bile.

Mechanism of Action

• Estrogens act through estrogen receptors, designated estrogen receptor alpha and estrogen receptor beta.
• Estrogen receptor alpha is abundant in the uterus, liver, kidney, and cardiovascular tissues.
• Estrogen receptor beta is found predominantly in the ovaries, brain, gastrointestinal tract, lungs, and hematopoietic tissues.
• After binding to intracellular receptors, estrogen regulates gene transcription and protein synthesis through genomic mechanisms.
• Estrogens also produce rapid nongenomic actions through membrane-associated receptors and intracellular signaling pathways.
• Most physiological effects of estrogen are mediated by genomic mechanisms.

Physiological Actions

Effects on Female Reproductive System

• Estrogen promotes the growth, maturation, and functional development of the female reproductive tract.
• It stimulates proliferation of epithelial tissues and growth of smooth muscle in reproductive organs.

On ovary

• Estrogen supports the growth and maturation of ovarian follicles.
• It contributes to follicular development by enhancing the responsiveness of ovarian cells to gonadotropins.
• It also helps maintain normal ovarian structure and function.

On Fallopian Tubes

• Estrogen increases the motility of the fallopian tubes by stimulating smooth muscle activity.
• It enhances the frequency and force of ciliary beating in the tubal epithelium.
• These actions facilitate transport of the ovum and aid movement of sperm toward the site of fertilization.

On Uterus

• Estrogen promotes enlargement of the uterus during puberty and the reproductive years.
• It stimulates proliferation of the endometrium during the follicular phase of the menstrual cycle.
• It increases uterine blood flow and supports growth of the myometrium.
• Estrogen induces synthesis of progesterone receptors in the endometrium, thereby preparing the uterus for the actions of progesterone during the luteal phase.
• Along with progesterone, it contributes to uterine glandular secretion during the secretory phase.
• Estrogen increases the synthesis of contractile proteins in uterine smooth muscle.
• It enhances myometrial excitability and increases uterine sensitivity to oxytocin.
• Near term, rising estrogen levels help prepare the uterus for labor.

Effects on Cervical Mucous

• Estrogen increases the quantity of cervical mucus.
• The mucus becomes thin, clear, and less viscous around ovulation.
• These changes facilitate sperm penetration through the cervix and improve the likelihood of fertilization.

Effects on Breast

• Estrogen plays a major role in breast development during puberty.
• It stimulates growth and branching of the mammary ducts.
• It promotes deposition of adipose tissue within the breasts, contributing to breast enlargement.
• Estrogen causes pigmentation and enlargement of the areola and nipple.
• Although estrogen promotes breast growth, full development of the mammary glands requires the coordinated actions of progesterone, growth hormone, prolactin, and other hormones.

Effects on Secondary Sexual Characteristics

• Estrogen is primarily responsible for the development of secondary sexual characteristics at puberty.
• It contributes to the characteristic female body shape, with relatively broader hips and narrower shoulders.
• It promotes deposition of subcutaneous fat, particularly in the breasts, hips, buttocks, and thighs.
• The pelvis enlarges and widens, facilitating childbirth in adulthood.
• The carrying angle of the elbow is generally greater in females than in males.
• Estrogen helps maintain soft and smooth skin with a relatively thin texture.
• Female voice remains relatively high-pitched because the larynx undergoes only limited enlargement during puberty.
• It promotes growth and maturation of the uterus, vagina, fallopian tubes, and ovaries.
• Pubic and axillary hair growth is influenced mainly by adrenal and ovarian androgens rather than by estrogen.
• In females, pubic hair typically shows a triangular distribution with the base directed upward.

Effects on Endocrine Organs

• Estrogen regulates the hypothalamo-pituitary-ovarian axis through feedback mechanisms.
• At low to moderate concentrations, it suppresses gonadotropin secretion by reducing gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone release.
• Sustained high estrogen levels before ovulation produce positive feedback, resulting in the luteinizing hormone surge.
• Estrogen stimulates prolactin secretion from the anterior pituitary gland.
• During pregnancy, high estrogen levels promote growth of the mammary glands but inhibit active milk secretion.
• Estrogen increases hepatic synthesis of angiotensinogen, which can contribute to activation of the renin–angiotensin system.
• It increases the production of thyroxine-binding globulin and several other plasma-binding proteins.
• Estrogen may enhance adrenal androgen production to a limited extent.

Effects on CNS

• Estrogen influences several regions of the central nervous system, particularly the hypothalamus and limbic system.
• It contributes to sexual motivation, reproductive behavior, mood regulation, and emotional well-being.
• Estrogen also participates in the feedback regulation of reproductive hormone secretion.

Effects on Musculoskeletal System

• Estrogen promotes normal skeletal growth and maintenance.
• It inhibits osteoclast-mediated bone resorption and helps preserve bone mass.
• Adequate estrogen levels reduce the risk of osteoporosis and fragility fractures.
• Estrogen accelerates epiphyseal plate closure at puberty, thereby limiting further longitudinal bone growth.
• It has no major direct anabolic effect on skeletal muscle but may indirectly support muscle development through metabolic and hormonal influences.

Effects on Water and Electrolyte Metabolisms

• Estrogen can promote mild retention of sodium and water by acting on the kidneys.
• It also enhances activity of the renin–angiotensin–aldosterone system through increased angiotensinogen synthesis.
• These effects may contribute to fluid retention during pregnancy or estrogen therapy.

Effects on Lipid Profile

• Estrogen improves the lipid profile by reducing low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol.
• These effects contribute to a lower risk of atherosclerosis and coronary artery disease during the reproductive years.

Effects on Sebaceous Secretion & Skin

• Estrogen promotes skin thickness, elasticity, and vascularity.
• It increases skin hydration by enhancing water retention in the dermis.
• Estrogen reduces sebaceous gland activity and counteracts androgen-induced sebum production.
• These actions may decrease the tendency for acne formation.
• Prolonged exposure to high estrogen levels may be associated with the development of spider angiomas.

Estrogen Preparations

• Estrogen preparations include natural estrogens, synthetic estrogens, and selective estrogen receptor modulators.
• Selective estrogen receptor modulators produce estrogen-like effects in some tissues while blocking estrogen action in others.
• Tamoxifen acts mainly as an estrogen antagonist in breast tissue.
• Raloxifene helps preserve bone mass and reduces the risk of osteoporosis while exerting minimal stimulatory effects on the endometrium.

Progesterone

Source, Synthesis and Metabolism

• Progesterone is secreted mainly by the corpus luteum and placenta. Small amounts are also produced by developing ovarian follicles and the adrenal cortex.
• It is a steroid hormone synthesized from cholesterol through pregnenolone.
• Plasma progesterone concentration is low during the follicular phase and rises markedly during the luteal phase.
• Most circulating progesterone is bound to plasma proteins, primarily albumin and corticosteroid-binding globulin.
• Only a small fraction circulates in the free, biologically active form.
• Progesterone is metabolized mainly in the liver to pregnanediol and other metabolites.
• These metabolites are conjugated and excreted in urine.

Mechanism of Action

• Progesterone acts through intracellular progesterone receptors.
• he hormone–receptor complex regulates gene transcription and protein synthesis, producing most of its physiological effects.

Physiological Actions

Effects on Reproductive Organs

• Progesterone is essential for the establishment and maintenance of pregnancy.
• It suppresses uterine contractions and promotes uterine quiescence throughout gestation.
• Progesterone opposes the contractile effects of estrogen and locally produced prostaglandins on the myometrium.
• It directly relaxes uterine smooth muscle and reduces myometrial excitability.
• It decreases the sensitivity of the uterus to oxytocin, thereby reducing the likelihood of premature contractions.
• These actions facilitate implantation and help prevent spontaneous abortion.
• Progesterone acts on the estrogen-primed endometrium and converts it into a secretory endometrium suitable for implantation.
• It stimulates secretion from endometrial glands and supports early embryonic nutrition.
• Progesterone makes cervical mucus thick, viscid, and less permeable to sperm and microorganisms.
• This cervical mucus barrier helps protect the uterine cavity from ascending infections.
• It reduces proliferation of the vaginal epithelium and promotes secretory changes.

Effects on Breast

• Progesterone promotes growth and differentiation of mammary glandular tissue.
• It stimulates development of lobules and alveoli in the breast.
• It acts together with estrogen to prepare the breast for lactation.
• Although it supports mammary development, milk secretion is initiated mainly after delivery when progesterone levels fall.

Effects on Body Temperature

• Progesterone has a thermogenic effect on the hypothalamus.
• Basal body temperature rises by approximately 0.3–0.5°C after ovulation and remains elevated during the luteal phase.

Effects on Hypothalamo-Pituitary Axis

• Progesterone exerts negative feedback on the hypothalamus and anterior pituitary gland.
• It suppresses gonadotropin-releasing hormone secretion and reduces luteinizing hormone release.
• In combination with estrogen, it inhibits ovulation and forms the basis of many hormonal contraceptive methods.

Effects on Respiration

• Progesterone stimulates the respiratory center and increases alveolar ventilation.
• As a result, arterial carbon dioxide tension decreases slightly during pregnancy.

Effects on Blood Pressure

• Progesterone relaxes vascular smooth muscle and promotes vasodilation.
• This effect contributes to the reduction in systemic vascular resistance observed during normal pregnancy.

On Electrolyte and Water Metabolisms

• Progesterone has mild anti-mineralocorticoid activity.
• It antagonizes aldosterone action in the kidneys and promotes sodium excretion.
• These effects may contribute to mild natriuresis and increased urine output.

Other Ovarian Hormones

Relaxin

Relaxin is a peptide hormone structurally related to the insulin family of peptides.

Source

• In females, it is produced mainly by the corpus luteum, placenta, decidua, and breast tissue.
• In males, relaxin is secreted by the prostate gland.
• Relaxin levels increase during pregnancy and reach their highest values near term.

Functions

• Relaxin promotes relaxation of pelvic ligaments and the pubic symphysis.
• It softens and facilitates dilation of the cervix before childbirth.
• It reduces uterine contractility and helps maintain pregnancy.
• Relaxin contributes to growth and functional development of the mammary glands.
• In nonpregnant women, it is secreted during the luteal phase, although its physiological role remains incompletely understood.
• In males, relaxin may enhance sperm motility and facilitate fertilization.

Inhibins

• Inhibins are peptide hormones secreted primarily by granulosa cells of ovarian follicles.
• They exert negative feedback on the anterior pituitary gland and selectively suppress follicle-stimulating hormone secretion.
• Inhibins help regulate follicular development and ovarian function.

Androgens

• In females, androgens are produced by the ovaries and adrenal glands.
• They contribute to pubic and axillary hair growth and help maintain libido.
• Androgens also support normal musculoskeletal development.
• Excess androgen production may cause hirsutism, clitoromegaly, reduced breast size, and other features of virilization.

Control of Ovarian Functions

• The ovaries perform several essential reproductive and endocrine functions.
• They synthesize and secrete ovarian hormones, including estrogens, progesterone, inhibins, and relaxin.
• They support the growth and maturation of ovarian follicles and resident oocytes.
• They release a mature oocyte during ovulation.
• They prepare the fallopian tubes for transport of gametes and fertilization.
• They prepare the uterus for implantation and support early pregnancy until placental hormone production becomes adequate.
• Ovarian functions are regulated by the hypothalamo-pituitary-ovarian axis.
• The principal hormones involved are gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, and ovarian hormones.
• Coordinated interactions among these hormones ensure normal menstrual cyclicity and fertility.

Hypothalamic Control

• The hypothalamus regulates ovarian activity by controlling secretion of gonadotropins from the anterior pituitary gland.
• It secretes gonadotropin-releasing hormone in a pulsatile manner rather than continuously.
• Pulsatile hormone release is essential for normal secretion of luteinizing hormone and follicle-stimulating hormone.
• Continuous exposure to gonadotropin-releasing hormone suppresses pituitary responsiveness and reduces gonadotropin secretion.
• Variations in the frequency and amplitude of gonadotropin-releasing hormone pulses occur throughout the menstrual cycle.
• Changes in pulse frequency contribute to the cyclic pattern of gonadotropin secretion.
• Increased pulse frequency during the late follicular phase promotes the preovulatory luteinizing hormone surge.
• Pituitary sensitivity to gonadotropin-releasing hormone also increases near ovulation, facilitating this surge.
• Rising estrogen levels from the dominant follicle play a key role in triggering these changes.
• The luteinizing hormone surge induces ovulation and subsequent formation of the corpus luteum.
• Progesterone exerts inhibitory effects on gonadotropin-releasing hormone pulse frequency during the luteal phase.
• Androgens, endogenous opioid peptides, and certain neurotransmitters can also modulate hypothalamic activity.
• Thus, pulsatile hypothalamic hormone secretion serves as the primary regulator of ovarian function and reproductive cyclicity.

Pituitary Control

• The anterior pituitary gland secretes follicle-stimulating hormone and luteinizing hormone, collectively known as gonadotropins.
• These hormones act on the ovaries to regulate follicular development, ovulation, and ovarian hormone secretion throughout the menstrual cycle.

The Pattern of Secretion of Gonadotropins

• The secretion of follicle-stimulating hormone and luteinizing hormone varies throughout the menstrual cycle.
• Follicle-stimulating hormone levels rise slightly during the early follicular phase and promote recruitment of ovarian follicles.
• Its concentration gradually declines during the mid-follicular phase because of negative feedback from estrogen and inhibin.
• A smaller mid-cycle rise in follicle-stimulating hormone occurs around the time of ovulation.
• Luteinizing hormone remains at relatively low levels during most of the cycle.
• Approximately 24–36 hours before ovulation, luteinizing hormone secretion increases sharply, producing the luteinizing hormone surge.
• Following ovulation, luteinizing hormone levels decline during the luteal phase.

Regulation by FSH

• Primordial, primary, and early antral follicles are present in the ovaries throughout the reproductive years.
• Further growth of antral follicles depends on adequate follicle-stimulating hormone stimulation.
• Before puberty, low gonadotropin secretion limits follicular maturation.
• After puberty, follicle-stimulating hormone promotes proliferation of granulosa cells.
• It stimulates aromatase activity, leading to increased estrogen synthesis.
• Follicle-stimulating hormone also promotes enlargement of the follicular antrum and supports maturation of the dominant follicle.
• It increases the responsiveness of granulosa cells to luteinizing hormone during later stages of follicular development.

Regulation by LH

• Luteinizing hormone acts primarily on theca cells to stimulate androgen synthesis.
• These androgens are subsequently converted to estrogens by granulosa cells.
• Near ovulation, granulosa cells acquire receptors for luteinizing hormone and become increasingly responsive to its actions.
• The luteinizing hormone surge triggers ovulation and initiates formation of the corpus luteum.
• Luteinizing hormone also promotes luteinization of granulosa and theca cells, leading to progesterone secretion during the luteal phase.

The Ovarian Control

The ovary regulates its own activity through locally acting factors and feedback mechanisms involving ovarian hormones, the hypothalamus, and the pituitary gland.

The Pattern of Secretion of Gonadal Hormones

H5: Estrogen

• Estrogen levels remain relatively low during the early follicular phase.
• As the dominant follicle develops, estrogen secretion gradually increases and rises sharply during the late follicular phase.
• Peak estrogen concentration occurs approximately 24–48 hours before ovulation.
• Following ovulation, estrogen levels decline briefly.
• A smaller second rise occurs during the luteal phase because of secretion from the corpus luteum.

Progesterone

• Progesterone secretion remains low throughout the follicular phase.
• After ovulation, progesterone levels increase markedly because of production by the corpus luteum.
• Peak progesterone secretion occurs during the mid-luteal phase.

• Inhibin B secretion increases during the follicular phase and contributes to suppression of follicle-stimulating hormone secretion.

Direct Regulation

• Theca cells synthesize androgen precursors under the influence of luteinizing hormone.
• These androgens diffuse into granulosa cells, where they are converted into estrogens by the enzyme aromatase.
• This coordinated interaction between theca and granulosa cells is essential for normal follicular development and estrogen production.

Feedback Regulation

• Ovarian hormones regulate reproductive function through feedback effects on the hypothalamo-pituitary-ovarian axis.
• During most of the menstrual cycle, low to moderate estrogen concentrations suppress gonadotropin-releasing hormone, follicle-stimulating hormone, and luteinizing hormone secretion through negative feedback.
• Sustained high estrogen levels during the late follicular phase switch to a positive feedback effect.
• This positive feedback stimulates the preovulatory luteinizing hormone surge that triggers ovulation.
• The precise mechanisms responsible for this switch from negative to positive feedback are not completely understood but involve both hypothalamic and pituitary pathways.
• Progesterone exerts negative feedback on gonadotropin secretion, particularly luteinizing hormone.
• Progesterone enhances the inhibitory effects of estrogen on the hypothalamus and pituitary gland.
• This principle forms the physiological basis of combined hormonal contraceptives, which suppress ovulation.
• Inhibin, secreted by granulosa cells and the corpus luteum, selectively suppresses follicle-stimulating hormone secretion.
• During the luteal phase, elevated progesterone, estrogen, and inhibin levels keep gonadotropin concentrations low.
• Thus, ovarian hormones not only mediate reproductive functions but also regulate the activity of the hypothalamus and anterior pituitary through powerful feedback mechanisms.

Applied Aspects

Genetic and Hormonal Abnormalities

Ovarian dysfunction may result from genetic defects, hormonal abnormalities, or abnormalities of hormone receptors.

GnRH Resistance

Gonadotropin-releasing hormone resistance occurs because of impaired receptor function in pituitary gonadotrophs, leading to reduced gonadotropin secretion.

FSH Resistance

Follicle-stimulating hormone resistanceresults from defective or reduced follicle-stimulating hormone receptors on granulosa cells, causing impaired follicular development and infertility.

LH Resistance

• Luteinizing hormone resistance occurs because of abnormalities in luteinizing hormone receptors on theca or granulosa cells.
• These disorders may lead to anovulation, menstrual irregularities, delayed puberty, or subfertility.

Aromatase Deficiency

• Aromatase is the enzyme that converts androgens into estrogens.
• Deficiency of aromatase results in reduced estrogen synthesis and excess androgen activity.
• Affected females may develop delayed puberty, primary amenorrhea, infertility, and varying degrees of virilization.

McCune-Albright Syndrome

• McCune–Albright syndrome is caused by an activating mutation of the GNAS gene, leading to abnormal G-protein signaling.
• It is characterized by endocrine hyperfunction, precocious puberty, café-au-lait skin pigmentation, and fibrous dysplasia of bone.
• Menstrual abnormalities may occur later in life.

Kallmann’s Syndrome

• Kallmann syndrome results from impaired migration of gonadotropin-releasing hormone-producing neurons during fetal development.
• It causes deficient gonadotropin-releasing hormone secretion, leading to hypogonadotropic hypogonadism.
• Delayed or absent puberty and reduced sense of smell are characteristic features.