BIOCHEMICAL ASPECTS OF MALE

REPRODUCTIVE HORMONES

Dr. Bijaya Mishra

Assistant Professor
Department of Biochemistry
Date: 19/07/2023
Objective
 Introduction

 Hormones of Hypothalamic- Pituitary- Gonadotrophic Axis

 Gonadotropin Hormones in Males

 Androgen- Testosterone Biosynthesis, Metabolism

 Regulation

 Clinical aspects
Male reproductive biology
• Mature testes synthesize:- sperm and androgens.

• Testes contains structured network of tightly packed seminiferous tubules:-

lumen lined by maturing germ cells and Sertoli cells- sperm maturation.

• Surrounding seminiferous tubules- interstitial Leydig cells- primary site for

androgen (testosterone) production.

• Testosterone- sexual differentiation, spermatogenesis, promotion and

maintenance of sexual maturity at puberty.

• Cellular level- effects mediated by binding of testosterone or DHT to

androgen receptor.
Introduction

Leydig cells- almost nonexistent

during childhood, secrete almost
no testosterone.
Numerous in entire fetal
development and newborn male
infant for first few months of life
(10wks) and in adult male after
puberty.
Introduction..
• Reproductive endocrinology encompasses hormones of
hypothalamic-pituitary-gonadal axis; adrenal glands.

• Hormones crucial for reproductive function- GnRH, lutenizing

hormone (LH), follicle stimulating hormone (FSH), sex steroids
synthesized by ovaries, testes, adrenal glands, responsible for
manifestation of primary and secondary sex characteristics-
normal male and female sexual development, sexual function and
fertility.
Gonadotropn
i -ree
l asn
i ghormone(GnRH)

• Decapeptide, synthesized by hypothalamus.

• Transported to ant pituitary gonadotrophs cells activates receptors

(GPCR) stimulates phosphoinositide phospholipase C mobilize
calcium and PKC activation of proteins involved in synthesis and
release of LH and FSH.

• Pulsatile patterns- peaks every 90 mins; t1/2 ~2-4mins.

• Pathway of hormones in male from hypothalamus to pituitary gland to

target organ is :
-Hypothalamus→ GnRH → Pituitary → LH → Testes →Testosterone
-Hypothalamus→ GnRH → Pituitary → FSH → Testes → Spermatogenesis
LH and FSH
LH and FSH exert effect on target tissues in testes mainly by activating cAMP second
messenger system; t1/2 FSH is ~4 h; t1/2 LH is ~20 min.

 LH: stimulates interstitial (Leydig) cells to secrete testosterone hormone (direct

proportion).

 Main function of LH in males- determining secondary sexual characteristics by

stimulating testosterone secretion.

 FSH stimulates Sertoli cells in seminiferous tubules to grow and secrete various
spermatogenesis substances (ABP).

 Testosterone and DHT diffuse into seminiferous tubules to act on spermatogenesis.

 Leydig cells are almost nonexistent in testes during childhood: the testes secrete
Male sex hormones- Androgens
• Testes secrete several male sex hormones- collectively known
Androgen:- testosterone, dihydrotestosterone and
androstenedione.

• Biosynthesis: primarily in Leydig cells (95%); ~5% via peripheral

conversion from dehroepiandrosterone (DHEA) and
androstenedione- adrenals (zona reticularis).

• Major androgen or androgen precursor produced by adrenal

cortex: DHEA
 Biosynthesis of Testosterone

• Androgens- steroid compounds; synthesis begins either with

mobilization of cholesterol derived from lipoprotein or by de novo
synthesis from acetyl CoA.

• Cholesterol released from lipid droplets migrates to inner

mitochondrial membrane where pregnenolone formed (rate limiting
steps); however, rate of steroidogeneis is determined by delivery of
cholesterol to IMM by steroidogenic regulatory protein (StAR)-
regulated by LH.

• Pregnenolone- translocated to SER; five additional enzymatic steps

 Testosterone Biosynthesis
• Step 1: Cholesterol to Pregnenolone.
• This is the point where LH primarily regulates steroidogenesis

Cholesterol SCC enzyme (CYP-450): P450scc: occurs in mitochondrial complex

a. 20α- hydroxylase
b. 22- hydroxylase
c. 20,22-lyase
Two pathways for testosterone biosynthesis
Biosynthesis contd..
Pregnenolone to testosterone requires action of five enzyme activities contained in three
proteins:

(1) 3β-hydroxysteroid dehydrogenase (3β-OHSD) and Δ5,4-isomerase: pregnenolone to

progesterone.

(2) 17α-hydroxylase and 17,20-lyase: 17α-hydroxylation to 17-OH pregnenolone and 17-OH

progesterone dehydroepiandrosterone (DHEA) and androstenedione respectively.

(3) 17β-hydroxysteroid dehydrogenase (17β-OHSD):- androstenedione testosterone

This sequence:- progesterone (or Δ4) pathway.

Pregnenolone converted to testosterone by dehydroepiandrosterone (or Δ5)- most used in

human testes.
Androgen transport in the blood
Testosterone and DHT circulate in plasma either:

Free (approximately 2% to 3%) or

Bound to plasma proteins
Tightly bound to specific sex hormone-binding globulin (SHBG)~80%

Weakly bound to albumin.

Circulates in blood in these states for ~30 mins to several hours. By this
time, testosterone is either transferred to tissues or degraded into inactive
products that are subsequently excreted.
 Metabolism of Testosterone

DHT-cause for BPH- affects >75% of men

over 60 years age.
Rx: Fenasteride
Metabolism of Testosterone
Testosterone:- Plasma Testosterone
pro-hormone
(5mg/day)
Aromatase Hydroxylases
Plasma Estradiol: (0.02
mg/d)(peripheral
5 α Reductase 17 β-OH Polar
(NADPH dependent)
aromatization) SDH metabolites
 BMD, epiphyseal fusion, bone
reabsorption, mood and cognition, HDL (2.5mg/day)

Plasma Dihydrotestosterone (DHT)- 17 –Ketosteroids

active form; (0.4 mg/d) (2.0 mg/day): many
Prostratic growth, external genitalia, some area of
skin, hair follicle in androgen sensitive area tissues, mainly liver
Effect on target tissue: activation of
androgen receptor (directly or as DHT- binds
strongly), and by conversion to estradiol (E2)
and activation of certain estrogen receptors

*Bone and brain- primary effect of testosterone is by

way of aromatization to E2.

Bone- E2 accelerates maturation of cartilage into bone,

leading to closure of epiphyses and conclusion of
growth.

CNS- E2 rather than testosterone serves as most

important feedback signal to hypothalamus (specially
 Functions of Androgens
During embryonic development
At 8th WOG, both ducts; differing only by Y chr

Testosterone and DHT

• Testosterone induce the Wolffian duct

• DHT induces external genitalia.

• Just before birth causes descent of testes

from abdominal cavity into scrotal sac.

Leydig cells are stimulated by phCG to secrete testosterone from 9 th
WOG, leading to development of Wolffian ducts.

Sertoli cells secrete AMH, which causes regression of Müllerian ducts and
oogonia.
In absence of AMH and testosterone, Müllerian ducts differentiate into
female internal genitalia.
 Functions of Androgens contd…
During puberty, testosterone:
Promotes somatic growth ;

Stimulates enlargement of testes & accessory organs

Development of secondary sex characteristics.

 Deepening of voice,
 Increase of muscle mass, and libido.
 Increased growth of body hair
 Enlargement of larynx & thickening of vocal cords
 Functions of Androgens contd…

In adults, testosterone necessary for :

• Spermatogenesis

• Stimulation of libido, normal sexual function

• Maintenance of muscle and bone mass.

• Increases- protein formation, muscle development, bone
matrix, calcium retention
• Strengths pelvis for load bearing;

• Increases- BMR; RBC; reabsorption of sodium in DCT

Role of testosterone in Spermatogenesis
• LH binds to interstitial cells causing
them to secrete testosterone.

• FSH binds Sertoli cells (basement

membrane cells of seminiferous tubules)
and promotes synthesis of androgen
binding protein (ABP); which promotes
testosterone binding to spermatogenic
cells spermatogenesis
 Regulation: Hypothalamic-Pituitary-Gonadal Axis.

• GnRH -activation of proteins involved in synthesis of LH

and FSH.

• LH- Leydig cells, stimulate conversion of cholesterol to

pregnenolone testosterone (direct proportion).

• FSH- Sertoli cells and spermatocytes; both FSH and

testosterone and DHT required.

• Sex steroid (testosterone, E2, DHT) and inhibin provide

negative feedback control of LH and FSH secretion,
respectively.

• In adrenal gland ACTH stimulates androgen synthesis

 Regulation..

• Testosterone, E2:- inhibits LH, lesser extent FSH secretion.

• Prolactin- inhibits direct action of gonadotrophins on testes.

• Inhibin B produced by Sertoli cells, inhibits FSH production;
activin enhance FSH action, increasing spermatogenesis.

• Spermatogenesis too rapid FSH decreases markedly- negative

feedback due to inhibin.
• Seminiferous tubule fail to produce sperm- secretion of FSH
increases markedly.

• Inhibin B- marker for male infertility- concn directly reflects

function of Sertoli cells: plasma inhibin B significantly higher in
fertile men.
 Testosterone secretion by age
• When accompanied by symptoms of T decreased-
hot flashes, libido, sexual dysfunction, energy levels,
muscle mass-BMD, change in mood- regarded as
syndrome, variety of names:-
• Androgen deficiency in the aging male (ADAM)
• Partial androgen deficiency of the aging male
(PADAM)
• Late-onset hypogonadism (LOH)
• Andropause (erroneously)
• Testosterone deficiency syndrome; male
climacteric
Male hormones disorders
• Abnormal puberty- very early (precocious) or late onset (delayed), usually due
to hormonal imbalance.
• Precocious puberty- overproduction of hormones.
• Delayed puberty- familial, underproduction of hormones; tumor pressing hypothalamus,
Klinefelter’s syndrome-sex organs do not grow normally.

• Infertility: Small % caused by hormonal problems; fail/disruption to release

GnRH; pituitary failure- no enough LH, FSH; testes- Leydig cells not produce
testosterone.

• Gynecomastia: noncancerous enlargement of one/both breast in male; too much

estrogen
• Common-newborn boys, affects 1 in 2 adolescents- fetus exposed to mothers estrogen;
spironolactone, corticosteroid.
• Testicular failure estrogen/ androgen ratio
Hypogonadism
Male hypogonadism (testosterone deficiency)- failure of testes to produce
testosterone, sperm, or both; can be due to testicular disorder or result of
disease process involving hypothalamus & pituitary gland.

Klinefelter’s (47,XXY or XXY): set of

symptoms that result from two or more X chr
in males; primary features- infertility; small
testicles.

Kallmann’s syndrome: form of

hypogonadotropic hypogonadism,
characterized by delayed or absent
puberty and impaired sense of smell.
Anabolic Steroids
• Synthetic androgens – higher anabolic but lower androgenic activity (1: 3 ratio)
• Similar anabolic effect, same receptors.
• Eg: Nandrolone propionate; Nandrolone decanoate; Stanazolol
• Uses: catabolic states: acute illness, severe trauma, major surgery; renal
insufficiency; osteoporosis; suboptimal growth in boys; anemia; perfomance
enhancement.

• Side effects from anabolic steroids:

shrinking of testicles, breast enlargement (gynecomastia),low sperm count,
increased hair growth, deeper voice and reduced breast size in women, high blood
pressure, heart attack, stroke.